Benzoxazole kinase inhibitors and methods of use

ABSTRACT

The present invention provides chemical entities or compounds and pharmaceutical compositions thereof that are capable of modulating certain protein kinases such as mTor, tyrosine kinases, and/or lipid kinases such as PI3 kinase. Also provided in the present invention are methods of using these compositions to modulate activities of one or more of these kinases, especially for therapeutic applications.

This application is a Divisional application which claims the benefit ofU.S. application Ser. No. 12/586,309, filed Sep. 17, 2009; which claimsthe benefit of U.S. Provisional Application Ser. No. 61/198,200, filedon Nov. 3, 2008; U.S. Provisional Application Ser. No. 61/201,923, filedDec. 16, 2008; U.S. Provisional Application Ser. No. 61/214,261, filedApr. 20, 2009; and U.S. Provisional Application Ser. No. 61/230,655,filed Jul. 31, 2009, each of which is hereby incorporated by referencein its entirety.

BACKGROUND OF THE INVENTION

The activity of cells can be regulated by external signals thatstimulate or inhibit intracellular events. The process by whichstimulatory or inhibitory signals are transmitted into and within a cellto elicit an intracellular response is referred to as signaltransduction. Over the past decades, cascades of signal transductionevents have been elucidated and found to play a central role in avariety of biological responses. Defects in various components of signaltransduction pathways have been found to account for a vast number ofdiseases, including numerous forms of cancer, inflammatory disorders,metabolic disorders, vascular and neuronal diseases (Gaestel et al.Current Medicinal Chemistry (2007) 14:2214-2234).

Kinases represent a class of important signaling molecules. Kinases cangenerally be classified into protein kinases and lipid kinases, andcertain kinases exhibit dual specificities. Protein kinases are enzymesthat phosphorylate other proteins and/or themselves (i.e.,autophosphorylation). Protein kinases can be generally classified intothree major groups based upon their substrate utilization: tyrosinekinases which predominantly phosphorylate substrates on tyrosineresidues (e.g., erb2, PDGF receptor, EGF receptor, VEGF receptor, src,abl), serine/threonine kinases which predominantly phosphorylatesubstrates on serine and/or threonine residues (e.g., mTorC1, mTorC2,ATM, ATR, DNA-PK, Akt), and dual-specificity kinases which phosphorylatesubstrates on tyrosine, serine and/or threonine residues.

Lipid kinases are enzymes that catalyze the phosphorylation of lipids.These enzymes, and the resulting phosphorylated lipids and lipid-derivedbiologically active organic molecules, play a role in many differentphysiological processes, including cell proliferation, migration,adhesion, and differentiation. Certain lipid kinases are membraneassociated and they catalyze the phosphorylation of lipids contained inor associated with cell membranes. Examples of such enzymes includephosphoinositide(s) kinases (such as PI3-kinases, PI4-Kinases),diacylglycerol kinases, and sphingosine kinases.

The phosphoinositide 3-kinases (PI3Ks) signaling pathway is one of themost highly mutated systems in human cancers. PI3K signaling is also akey factor in many other diseases in humans. PI3K signaling is involvedin many disease states including allergic contact dermatitis, rheumatoidarthritis, osteoarthritis, inflammatory bowel diseases, chronicobstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma,disorders related to diabetic complications, and inflammatorycomplications of the cardiovascular system such as acute coronarysyndrome.

PI3Ks are members of a unique and conserved family of intracellularlipid kinases that phosphorylate the 3′-OH group onphosphatidylinositols or phosphoinositides. The PI3K family comprises 15kinases with distinct substrate specificities, expression patterns, andmodes of regulation (Katso et al., 2001). The class I PI3Ks (p110α,p110β, p110δ, and p110γ) are typically activated by tyrosine kinases orG-protein coupled receptors to generatephosphatidylinositol-3,4,5-trisphosphate (PIP₃), which engagesdownstream effectors such as those in the Akt/PDK1 pathway, mTOR, theTec family kinases, and the Rho family GTPases. The class II and IIIPI3-Ks play a key role in intracellular trafficking through thesynthesis of PI(3)P and PI(3,4)P2. The PIKKs are protein kinases thatcontrol cell growth (mTORC1) or monitor genomic integrity (ATM, ATR,DNA-PK, and hSmg-1).

The production of PIP₃ initiates potent growth and survival signals. Insome epithelial cancers the PI3K pathway is activated by direct geneticmutation. As PI3K signaling pathway plays a pivotal role in cellproliferation and differentiation, inhibition of this pathway isbelieved to be beneficial in hyperproliferative diseases.

Downstream mediators of the PI3K signal transduction pathway include Aktand mammalian target of rapamycin (mTOR). Akt possesses a plckstrinhomology (PH) domain that bind PIP3, leading to Akt kinase activation.Akt phosphorylates many substrates and is a central downstream effectorof PI3K for diverse cellular responses. Full activation of Akt typicallyrequires phosphorylation of T308 in the activation loop and S473 in ahydrophobic motif. One important function of Akt is to augment theactivity of mTOR, through phosphorylation of TSC2 and other mechanisms.

mTOR is a serine-threonine kinase related to the lipid kinases of thePI3K family. mTOR has been implicated in a wide range of biologicalprocesses including cell growth, cell proliferation, cell motility andsurvival. Disregulation of the mTOR pathway has been reported in varioustypes of cancer. mTOR is a multifunctional kinase that integrates growthfactor and nutrient signals to regulate protein translation, nutrientuptake, autophagy, and mitochondrial function.

mTOR exists in two complexes, mTORC1 and mTORC2. mTORC1 contains theraptor subunit and mTORC2 contains rictor. These complexes aredifferentially regulated, and have distinct substrate specificities andrapamycin sensitivity. For example, mTORC1 phosphorylates S6 kinase(S6K) and 4EBP1, promoting increased translation and ribosome biogenesisto facilitate cell growth and cell cycle progression. S6K also acts in afeedback pathway to attenuate PI3K/Akt activation. mTORC2 is generallyinsensitive to rapamycin. mTORC2 is though to modulate growth factorsignaling by phosphorylating the C-terminal hydrophobic motif of someAGC kinases such as Akt. In many cellular contexts, mTORC2 is requiredfor phosphorylation of the S473 site of Akt.

Over the past decade, mTOR has drawn considerable attention due to itsrole in cell growth control and its involvement in human diseases. mTorhas been implicated in a wide range of disorders including but notlimited to cancer, diabetes, obesity, cardiovascular diseases andneurological disorders. It has been shown that mTOR modulates manyfundamental biological processes including transcription, translation,autophagy, actin organization and ribosome biogenesis by integratingintracellular and extracellular signals, such as signals mediated bygrowth factors, nutrients, energy levels and cellular stress.

As such, kinases particularly protein kinases such as mTor and Akt, aswell as lipid kinases such as PI3Ks are prime targets for drugdevelopment. The present invention addresses this need in the art byproviding a new class of kinase inhibitors.

SUMMARY OF THE INVENTION

In one aspect of the invention, compounds are provided of the FormulaI′-A′:

or a pharmaceutically acceptable salt thereof, wherein:

X₁ is N or C-E¹, X₂ is N, X₃ is C, and X₄ is C—R⁹ or N; or X₁ is N orC-E¹, X₂ is C, X₃ is N, and X₄ is C—R⁹ or N; and wherein no more thantwo nitrogen ring atoms are adjacent;

R₁ is H, -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl,-L-aryl, -L-heteroaryl, -L-C₁₋₁₀alkylaryl, -L-C₁₋₁₀alkylhetaryl,-L-C₁₋₁₀alkylheterocylyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl,-L-C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, -L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,-L-heteroalkyl, -L-heteroalkylaryl, -L-heteroalkylheteroaryl,-L-heteroalkyl-heterocylyl, -L-heteroalkyl-C₃₋₈cycloalkyl, -L-aralkyl,-L-heteroaralkyl, or -L-heterocyclyl, each of which is unsubstituted oris substituted by one or more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

M₁ is benzoxazolyl substituted with -(W²)_(k)-R²;

k is 0 or 1;

E¹ and E² are independently -(W¹)_(j)-R⁴;

j in E¹ or j in E², is independently 0 or 1;

W¹ is —O—, NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—, —CH(R⁷)N(C(O)OR⁸)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—;

W² is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)C(O)N(R⁸)—, —N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—,—CH(R⁷)N(C(O)OR⁸)—, —CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—,—CH(R⁷)C(O)N(R⁸)—, —CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or—CH(R⁷)N(R⁸)S(O)₂—;

R³ and R⁴ are independently hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³², aryl, hetaryl, C₁₋₄alkyl,C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl,C₃₋₈cycloalkyl-C₁₋₁₀alkyl, C₃₋₈cycloalkyl-C₂₋₁₀alkenyl,C₃₋₈cycloalkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkyl-C₂₋₁₀alkenyl,C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl, C₁₋₁₀alkylhetaryl,C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl,heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl C₂₋₁₀alkenyl, arylC₂₋₁₀alkynyl, aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, hetaryl C₂₋₁₀alkynyl, hetaryl C₃₋₈cycloalkyl,heteroalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein eachof said aryl or heteroaryl moiety is unsubstituted or is substitutedwith one or more independent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵,—NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

R⁵ is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³²;

R² is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,aryl (e.g. bicyclic aryl, unsubstituted aryl, or substituted monocyclicaryl), hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl,C₃₋₈cycloalkyl-C₁₋₁₀alkyl, C₃₋₈cycloalkyl-C₂₋₁₀alkenyl,C₃₋₈cycloalkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkyl-C₂₋₁₀alkenyl,C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl (e.g. C₂₋₁₀alkyl-monocyclicaryl, C₁₋₁₀alkyl-substituted monocyclic aryl, or C₁₋₁₀alkylbicycloaryl),C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl,C₂₋₁₀alkynylheteroalkyl, C₂₋₁₀alkynylheterocylyl,C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxy C₁₋₁₀alkyl,C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl, heterocyclyl,heteroalkyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl (e.g. monocyclicaryl-C₂₋₁₀alkyl, substituted monocyclic aryl-C₁₋₁₀alkyl, orbicycloaryl-C₁₋₁₀alkyl), aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl,hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl, hetaryl-heteroalkyl, orhetaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroarylmoiety is unsubstituted, or wherein each of bicyclic aryl, heteroarylmoiety or monocyclic aryl moiety is substituted with one or moreindependent alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo,—OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³²,—SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³,—NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³²,—NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³²,—OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³², and whereineach of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety isunsubstituted or is substituted with one or more alkyl, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—O-aryl, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or—C(═O)NR³¹R³²

each of R³¹, R³², and R³³ is independently H or C₁₋₁₀alkyl, wherein theC₁₋₁₀alkyl is unsubstituted or is substituted with one or more aryl,heteroalkyl, heterocyclyl, or hetaryl group, wherein each of said aryl,heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or issubstituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃, —O-aryl,—OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl),—NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl), —C(O)(C₁₋₁₀alkyl-aryl),—C(O)(aryl), —CO₂—C₁₋₁₀alkyl, —CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl,—C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵,—C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl), —O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂,—CN, S(O)₀₋₂C₁₋₁₀alkyl, —S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂ aryl,—SO₂N(aryl), —SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or—SO₂NR³⁴R³⁵;

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen atom;

each of R⁷ and R⁸ is independently hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,aryl, heteroaryl, heterocyclyl or C₃₋₁₀cycloalkyl, each of which exceptfor hydrogen is unsubstituted or is substituted by one or moreindependent R⁶;

R⁶ is halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl; aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, whereineach of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl,or hetaryl group is unsubstituted or is substituted with one or moreindependent halo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², or—NR³⁴R³⁵; and

R⁹ is H, halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl; aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, whereineach of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl,or hetaryl group is unsubstituted or is substituted with one or moreindependent halo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², or—NR³⁴R³⁵.

In some embodiments, X₄ is C—R⁹. In other embodiments, X₄ is N.

The invention also provides a compound as defined above, wherein thecompound is of Formula I-A:

or a pharmaceutically acceptable salt thereof, and wherein thesubstituents are as defined above.

In some embodiments of the compounds of Formula I′-A′ or I-A, X₃ is N.

In a second aspect, the invention provides a compound of Formula II-A-1:

or a pharmaceutically acceptable salt thereof, wherein:

X₁ is N or C-E¹ and X₂ is N; or X₁ is NH or CH-E¹ and X₂ is C;

R₁ is H, -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl,-L-aryl, -L-heteroaryl, -L-C₁₋₁₀alkylaryl, -L-C₁₋₁₀alkylhetaryl,-L-C₁₋₁₀alkylheterocylyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl,-L-C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, -L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,-L-heteroalkyl, -L-heteroalkylaryl, -L-heteroalkylheteroaryl,-L-heteroalkyl-heterocylyl, -L-heteroalkyl-C₃₋₈cycloalkyl, -L-aralkyl,-L-heteroaralkyl, -L-heterocyclyl, each of which is unsubstituted or issubstituted by one or more independent R³; and L is absent, —(C═O)—,—C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—, —S(O)₂N(R³¹)—, or—N(R³¹);

k is 0 or 1;

E¹ and E² are independently -(W¹)_(j)-R⁴;

j in E¹ or j in E², is independently 0 or 1;

W¹ is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—, —CH(R⁷)N(C(O)OR⁸)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—;

W² is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)C(O)N(R⁸)—, —N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—,—CH(R⁷)N(C(O)OR⁸)—, —CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—,—CH(R⁷)C(O)N(R⁸)—, —CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or—CH(R⁷)N(R⁸)S(O)₂—;

R² is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,aryl (e.g. bicyclic aryl, unsubstituted aryl, or substituted monocyclicaryl), hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl,C₃₋₈cycloalkyl-C₁₋₁₀alkyl, C₃₋₈cycloalkyl-C₂₋₁₀alkenyl,C₃₋₈cycloalkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkyl-C₂₋₁₀alkenyl,C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl (e.g. C₂₋₁₀alkyl-monocyclicaryl, C₁₋₁₀alkyl-substituted monocyclic aryl, or C₁₋₁₀alkylbicycloaryl),C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl,C₂₋₁₀alkynylheteroalkyl, C₂₋₁₀alkynylheterocylyl,C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxy C₁₋₁₀alkyl,C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl, heterocyclyl,heteroalkyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl (e.g. monocyclicaryl-C₂₋₁₀alkyl, substituted monocyclic aryl-C₁₋₁₀alkyl, orbicycloaryl-C₁₋₁₀alkyl), aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl,hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl, hetaryl-heteroalkyl, orhetaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroarylmoiety is unsubstituted, or wherein each of bicyclic aryl, heteroarylmoiety or monocyclic aryl moiety is substituted with one or moreindependent alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo,—OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³²,—SO₂NR³⁴R³⁵, NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³,—NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹, NR³¹C(═NR³²)NR³³R³²,—NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³²,—OC(═O)SR³¹, SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³², and whereineach of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety isunsubstituted or is substituted with one or more alkyl, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—O-aryl, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or—C(═O)NR³¹R³²;

R³ and R⁴ are independently hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³², aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₁₋₁₀alkyl-C₂₋₁₀alkenyl, C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl,C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl,heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl,heteroalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein eachof said aryl or heteroaryl moiety is unsubstituted or is substitutedwith one or more independent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵,—NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³² and wherein each of said alkyl, cycloalkyl, heterocyclyl,or heteroalkyl moiety is unsubstituted or is substituted with one ormore halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³², —NR³⁴R³⁵,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

each of R³¹, R³², and R³³ is independently H or C₁₋₁₀alkyl, wherein theC₁₋₁₀alkyl is unsubstituted or is substituted with one or more aryl,heteroalkyl, heterocyclyl, or hetaryl group, wherein each of said aryl,heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or issubstituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃, —O-aryl,—OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl),—NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl), —C(O)(C₁₋₁₀alkyl-aryl),C(O)(aryl), —CO₂—C₁₋₁₀alkyl, —CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl,—C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —C(═O)NH(C₁₋₁₀alkyl), C(═O)NR³⁴R³⁵,—C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl), —O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂,—CN, —S(O)₂C₁₋₁₀alkyl, S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂ aryl,—SO₂N(aryl), —SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or—SO₂NR³⁴R³⁵;

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen atom;

each of R⁷ and R⁸ is independently hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,aryl, heteroaryl, heterocyclyl or C₃₋₁₀cycloalkyl, each of which exceptfor hydrogen is unsubstituted or is substituted by one or moreindependent R⁶; and

R⁶ is halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl; or R⁶ is aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl,hetaryl-C₂₋₁₀alkynyl, each of which is unsubstituted or is substitutedwith one or more independent halo, cyano, nitro, —OC₁₋₁₀alkyl,C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵,—SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², or —NR³⁴R³⁵.

In a third aspect, the invention provides a compound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein:

X₁ is N or C-E¹ and X₂ is N; or X₁ is NH or CH-E¹ and X₂ is C;

R₁ is —H, -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl,-L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl, -L-aryl, -L-heteroaryl, -L-C₁₋₁₀alkylaryl,-L-C₁₋₁₀alkylhetaryl, -L-C₁₋₁₀alkylheterocylyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₂₋₁₀alkenyl-C₃₋₈cycloalkyl,-L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl, -L-heteroalkyl, -L-heteroalkylaryl,-L-heteroalkylheteroaryl, -L-heteroalkyl-heterocylyl,-L-heteroalkyl-C₃₋₈cycloalkyl, -L-aralkyl, -L-heteroaralkyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

M₁ is benzoxazolyl substituted with -(W²)_(k)-R²;

k is 0 or 1;

E¹ and E² are independently -(W¹)_(j)-R⁴;

j in E¹ or j in E², is independently 0 or 1;

W¹ is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—, —CH(R⁷)N(C(O)OR)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—;

W² is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)C(O)N(R⁸)—, —N(R⁷)S(O)—, N(R⁷)S(O)₂—, —C(O)O—, —CH(R⁷)N(C(O)OR)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—;

R² is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,aryl (e.g. bicyclic aryl, unsubstituted aryl, or substituted monocyclicaryl), hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl,C₃₋₈cycloalkyl-C₁₋₁₀alkyl, C₃₋₈cycloalkyl-C₂₋₁₀alkenyl,C₃₋₈cycloalkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkyl-C₂₋₁₀alkenyl,C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl (e.g. C₂₋₁₀alkyl-monocyclicaryl, C₁₋₁₀alkyl-substituted monocyclic aryl, or C₁₋₁₀alkylbicycloaryl),C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl,C₂₋₁₀alkynylheteroalkyl, C₂₋₁₀alkynylheterocylyl,C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxy C₁₋₁₀alkyl,C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl, heterocyclyl,heteroalkyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl (e.g. monocyclicaryl-C₂₋₁₀alkyl, substituted monocyclic aryl-C₁₋₁₀alkyl, orbicycloaryl-C₁₋₁₀alkyl), aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl,hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl, hetaryl-heteroalkyl, orhetaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroarylmoiety is unsubstituted, or wherein each of bicyclic aryl, heteroarylmoiety or monocyclic aryl moiety is substituted with one or moreindependent alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo,—OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³²,—SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³,—NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³²,—NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³²,—OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³², and whereineach of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety isunsubstituted or is substituted with one or more alkyl, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—O-aryl, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or—C(═O)NR³¹R³²;

R³ and R⁴ are independently hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³², aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₁₋₁₀alkyl-C₂₋₁₀alkenyl, C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl,C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl,heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₁₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl,heteroalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein eachof said aryl or heteroaryl moiety is unsubstituted or is substitutedwith one or more independent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵,—NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

each of R³¹, R³², and R³³ is are independently H or C₁₋₁₀alkyl, whereinthe C₁₋₁₀alkyl is unsubstituted or is substituted with one or more aryl,heteroalkyl, heterocyclyl, or hetaryl group, wherein each of said aryl,heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or issubstituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃, —O-aryl,—OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl),—NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl), C(O)(C₁₋₁₀alkyl-aryl),—C(O)(aryl), —CO₂—C₁₋₁₀alkyl, —CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl,—C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵,—C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl), —O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂,—CN, —S(O)₀₋₂C₁₋₁₀alkyl, —S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂aryl,—SO₂N(aryl), —SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) orSO₂NR³⁴R³⁵;

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen atom;

each of R⁷ and R⁸ is independently hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,aryl, heteroaryl, heterocyclyl or C₃₋₁₀cycloalkyl, each of which exceptfor hydrogen is unsubstituted or is substituted by one or moreindependent R⁶;

R⁶ is halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl; aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, whereineach of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl,or hetaryl group is unsubstituted or is substituted with one or moreindependent halo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², or—NR³⁴R³⁵; and

R⁹ is H, halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl; aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, whereineach of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl,or hetaryl group is unsubstituted or is substituted with one or moreindependent halo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², or—NR³⁴R³⁵.

In yet another aspect, the invention provides a compound of FormulaIV-A-1:

or a pharmaceutically acceptable salt thereof wherein:

X₁ is N or C-E¹ and X₂ is N; or X₁ is NH or CH-E¹ and X₂ is C;

R₁ is H, -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl,-L-aryl, -L-heteroaryl, -L-C₁₋₁₀alkylaryl, -L-C₁₋₁₀alkylhetaryl,-L-C₁₋₁₀alkylheterocylyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl,-L-C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, -L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,-L-heteroalkyl, -L-heteroalkylaryl, -L-heteroalkylheteroaryl,-L-heteroalkyl-heterocylyl, -L-heteroalkyl-C₃₋₈cycloalkyl, -L-aralkyl,-L-heteroaralkyl, or -L-heterocyclyl, each of which is unsubstituted oris substituted by one or more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

E¹ and E² are independently -(W¹)_(j)-R⁴;

j in E¹ or j in E², is independently 0 or 1;

W¹ is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)S(O)—, —N(R⁷)S(O)₂, —C(O)O—, —CH(R⁷)N(C(O)OR⁸)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—;

W² is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)C(O)N(R⁸)—, —N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—,—CH(R⁷)N(C(O)OR⁸)—, —CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—,—CH(R⁷)C(O)N(R⁸)—, —CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or—CH(R⁷)N(R⁸)S(O)₂—;

k is 0 or 1;

R², R³ and R⁴ are independently hydrogen, halogen, —OH, —R³¹, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₀₋₂NR³¹R³², —SO₀₋₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═OO)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³², aryl (e.g. bicyclic aryl,unsubstituted aryl, or substituted monocyclic aryl), hetaryl,C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl,C₃₋₈cycloalkyl-C₁₋₁₀alkyl, C₃₋₈cycloalkyl-C₂₋₁₀alkenyl,C₃₋₈cycloalkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkyl-C₂₋₁₀alkenyl,C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl (e.g. C₂₋₁₀alkyl-monocyclicaryl, C₁₋₁₀alkyl-substituted monocyclic aryl, or C₁₋₁₀alkylbicycloaryl),C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl,C₂₋₁₀alkynylheteroalkyl, C₂₋₁₀alkynylheterocylyl,C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxy C₁₋₁₀alkyl,C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl, heterocyclyl,heteroalkyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl (e.g. monocyclicaryl-C₂₋₁₀alkyl, substituted monocyclic aryl-C₁₋₁₀alkyl, orbicycloaryl-C₁₋₁₀alkyl), aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl,hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl, hetaryl-heteroalkyl, orhetaryl-heterocyclyl, wherein each of said aryl or heteroaryl moiety isunsubstituted or is substituted with one or more independent alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³² and wherein each of saidalkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstitutedor is substituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

each of R³¹, R³², and R³³ is are independently H or C₁₋₁₀alkyl, whereinthe C₁₋₁₀alkyl is unsubstituted or is substituted with one or more aryl,heteroalkyl, heterocyclyl, or hetaryl group, wherein each of said aryl,heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or issubstituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃, —O-aryl,—OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl),—NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl), —C(O)(C₁₋₁₀alkyl-aryl),—C(O)(aryl), —CO₂—C₁₋₁₀alkyl, —CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl,—C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵,C(═O)NH₂, —OCF₃, O(C₁₋₁₀alkyl), —O-aryl, N(aryl)(C₁₋₁₀alkyl), —NO₂, —CN,—S(O)₀₋₂C₁₋₁₀alkyl, —S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂aryl, —SO₂N(aryl),—SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or —SO₂NR³⁴R³⁵;

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen atom;

each of R⁷ and R⁸ is independently hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,aryl, heteroaryl, heterocyclyl or C₃₋₁₀cycloalkyl, each of which exceptfor hydrogen is unsubstituted or is substituted by one or moreindependent R⁶;

R⁶ is halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl; aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, whereineach of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl,or hetaryl group is unsubstituted or is substituted with one or moreindependent halo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², or—NR³⁴R³⁵; and

R⁹ is H, halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl; aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, whereineach of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl,or hetaryl group is unsubstituted or is substituted with one or moreindependent halo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², or—NR³⁴R³⁵.

In another aspect, the invention provides a compound of Formula IV-A orFormula IV-B:

or pharmaceutically acceptable salt thereof, wherein:

X₁ is N or C-E¹, X₂ is N, X₃ is C, and X₄ is CR⁹ or N; or X₁ is N orC-E¹, X₂ is C, X₃ is N, and X₄ is CR⁹ or N;

R₁ is —H, -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl,-L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl, -L-aryl, -L-heteroaryl, -L-C₁₋₁₀alkylaryl,-L-C₁₋₁₀alkylhetaryl, -L-C₁₋₁₀alkylheterocylyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₂₋₁₀alkenyl-C₃₋₈cycloalkyl,-L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl, -L-heteroalkyl, -L-heteroalkylaryl,-L-heteroalkylheteroaryl, -L-heteroalkyl-heterocylyl,-L-heteroalkyl-C₃₋₈cycloalkyl, -L-aralkyl, -L-heteroaralkyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

k is 0 or 1;

E¹ and E² are independently -(W¹)_(j)-R⁴;

j in E¹ or j in E², is independently 0 or 1;

W¹ is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)S(O)—, —N(R⁷)S(O)₂, —C(O)O—, —CH(R⁷)N(C(O)OR⁸)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—;

W² is —O—, —NR⁷—, —S(O)₀₋₂, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)C(O)N(R⁸)—, —N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—,—CH(R⁷)N(C(O)OR⁸)—, —CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—,—CH(R⁷)C(O)N(R⁸)—, —CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or—CH(R⁷)N(R⁸)S(O)₂—;

R³ and R⁴ are independently hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³², aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkylC₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₁₋₁₀alkyl-C₂₋₁₀alkenyl, C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl,C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl,heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, hetaryl C₂₋₁₀alkynyl, hetaryl C₃₋₈cycloalkyl,heteroalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein eachof said aryl or heteroaryl moiety is unsubstituted or is substitutedwith one or more independent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵,—NO₂, —CN, —S(O)₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

R² is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,aryl (e.g. bicyclic aryl, unsubstituted aryl, or substituted monocyclicaryl), hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl,C₃₋₈cycloalkyl-C₁₋₁₀alkyl, C₃₋₈cycloalkyl-C₂₋₁₀alkenyl,C₃₋₈cycloalkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkyl-C₂₋₁₀alkenyl,C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl (e.g. C₂₋₁₀alkyl-monocyclicaryl, C₁₋₁₀alkyl-substituted monocyclic aryl, or C₁₋₁₀alkylbicycloaryl),C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl,C₂₋₁₀alkynylheteroalkyl, C₂₋₁₀alkynylheterocylyl,C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxy C₁₋₁₀alkyl,C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl, heterocyclyl,heteroalkyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl (e.g. monocyclicaryl-C₂₋₁₀alkyl, substituted monocyclic aryl-C₁₋₁₀alkyl, orbicycloaryl-C₁₋₁₀alkyl), aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl,hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl, hetaryl-heteroalkyl, orhetaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroarylmoiety is unsubstituted, or wherein each of bicyclic aryl, heteroarylmoiety or monocyclic aryl moiety is substituted with one or moreindependent alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo,—OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³²,—SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³,—NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³²,—NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³²,—OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³², and whereineach of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety isunsubstituted or is substituted with one or more alkyl, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—O-aryl, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or(═O)NR³¹R³²;

R⁵ is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³²;

each of R³¹, R³², and R³³ is independently H or C₁₋₁₀alkyl, wherein theC₁₋₁₀alkyl is unsubstituted or is substituted with one or more aryl,heteroalkyl, heterocyclyl, or hetaryl group, wherein each of said alkyl,aryl, heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or issubstituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃, —O-aryl,—OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl),—NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl), —C(O)(C₁₋₁₀alkyl-aryl),—C(O)(aryl), —CO₂—C₁₋₁₀alkyl, —CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl,—C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵,—C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl), —O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂,—CN, S(O)₀₋₂C₁₋₁₀alkyl, —S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂aryl,—SO₂N(aryl), —SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or—SO₂NR³⁴R³⁵;

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen atom;

each of R⁷ and R⁸ is independently hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,aryl, heteroaryl, heterocyclyl or C₃₋₁₀cycloalkyl, each of which exceptfor hydrogen is unsubstituted or is substituted by one or moreindependent R⁶;

R⁶ is halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl; aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, whereineach of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl,or hetaryl group is unsubstituted or is substituted with one or moreindependent halo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², or—NR³⁴R³⁵; and

R⁹ is H, halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl; aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, whereineach of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl,or hetaryl group is unsubstituted or is substituted with one or moreindependent halo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², or—NR³⁴R³⁵.

In one embodiment of the compounds of the invention, X₄ is CR⁹. Inanother embodiment, X₄ is N.

In some embodiments of the compounds of the invention, E² is —H. In someembodiments of the compounds of the invention, X₁ is N and X₂ is N. Inother embodiments of the compounds of the invention, X₁ is C-E¹ and X₂is N. In one embodiment of the compounds of the invention, X₁ is NH andX₂ is C.

In some embodiments of the compounds of the invention, R₃₁ and R₃₂ are—H.

In some embodiments of the compounds of Formula I′-A′, I-A, I-B, III(including III-A and III-B), C, or C″, M₁ is a benzoxazolyl moiety,substituted at the 2-position with -(W₂)_(k)-R₂. In some embodiments, M₁is either a 5-benzoxazolyl or a 6-benzoxazolyl moiety, optionallysubstituted with -(W₂)_(k)-R₂. In some embodiments, M₁ is either a5-benzoxazolyl or a 6-benzoxazolyl moiety, optionally substituted at its2-position with -(W₂)_(k)-R₂.

In some embodiments of the compounds of the invention, M₁ is a moietyhaving one of the following structures:

In some embodiments of the compounds of the invention, -(W²)_(k)- is—NR⁷, —N(R⁷)C(O)—, —N(R⁷)C(O)N(R⁸)—, or —N(R⁷)S(O)₂—. In otherembodiments of the compounds of the invention, -(W²)_(k)- is NH . Inanother embodiment of the compounds of the invention, -(W²)_(k)- is—(CH)₂—. In yet another embodiment of the compounds of the invention,-(W²)_(k)- is —NHC(O)—. In yet another embodiment of the compounds ofthe invention, -(W²)_(k)- is —N(R⁷)C(O)N(R⁸)—. In a further embodimentof the compounds of the invention, -(W²)_(k)- is —NHS(O)₂—.

In some embodiments of the compounds of the invention, R₁ is-L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkylheterocylyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³, wherein R³ is hydrogen, —OH, —OR³¹, —C(O)R³¹,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl,or heterocyclyl, wherein each of said aryl, heteroaryl, alkyl,cycloalkyl, or heterocyclyl moiety is unsubstituted or is substitutedwith one or more alkyl or —OH. In some embodiments of the compounds ofthe invention, R₁ is unsubstituted or is substituted with C₁₋₁₀alkyl orcycloC₁₋₁₀alkyl.

In some embodiments of the compounds of the invention, R² is —H. Inother embodiments of the compounds of the invention, R² is alkyl. In yetother embodiments of the compounds of the invention, R² is methyl. Inother embodiments of the compounds of the invention, R² is isopropyl. Insome embodiments of the compounds of the invention, R² is cycloalkyl. Inother embodiments of the compounds of the invention, R² is cyclopropyl.

In some embodiments of the compounds of the invention, E² is —H; X₁ andX₂ are N; R₁ is -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl,-L-C₁₋₁₀alkylheterocylyl, or -L-heterocyclyl, each of which isunsubstituted or is substituted by one or more independent R³; R³ ishydrogen, —OH, —OR³¹, —NR³¹R³², —C(O)R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵,aryl, hetaryl, C₁₋₄alkyl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, or heterocyclyl,wherein each of said aryl or heteroaryl moiety is unsubstituted or issubstituted with one or more independent alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², orSC(═O)NR³¹R³² s, and wherein each of said alkyl, cycloalkyl, orheterocyclyl moiety is unsubstituted or is substituted with one or morealkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃,—OCF₃, —OR³¹, —O-aryl, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²; and wherein -(W²)_(k) is —NR⁷—,—N(R⁷)C(O)— or —N(R⁷)S(O)₂—.

The invention also provides a process for synthesizing a compound ofFormula C:

comprising the step of allowing a compound of Formula A to react with acompound of Formula B under conditions that are effective forsynthesizing a compound of Formula C; wherein:

T₁ is halo;

X₁ is N or C-E¹, X₂ is N, and X₃ is C; or X₁ is N or C-E¹, X₂ is C, andX₃ is N; wherein no more than two ring nitrogen atoms of the compound ofFormula A are adjacent; and wherein no more than two ring nitrogen atomsof the compound of Formula C are adjacent;

R₁ is hydrogen, -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl,-L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl, -L-aryl, -L-heteroaryl, -L-C₁₋₁₀alkylaryl,-L-C₁₋₁₀alkylhetaryl, -L-C₁₋₁₀alkylheterocylyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₂₋₁₀alkenyl-C₃₋₈cycloalkyl,-L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl, -L-heteroalkyl, -L-heteroalkylaryl,-L-heteroalkylheteroaryl, -L-heteroalkyl-heterocylyl,-L-heteroalkyl-C₃₋₈cycloalkyl, -L-aralkyl, -L-heteroaralkyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

each of G is independently H or R_(G1); and R_(G1) is alkyl, alkenyl, oraryl;

or the G groups of

join together to form a 5- or 6-membered cyclic moiety;

M of Formula B is a M₁ moiety, and wherein M₁ moiety of Formula B and M₁moiety of Formula C are identical, having one of the followingstructures:

E¹ is -(W¹)_(j)-R⁴ wherein j is 0 or 1;

W¹ is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)S(O)—, —N(R⁷)S(O)₂, —C(O)O—, —CH(R⁷)N(C(O)OR⁸)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—;

k is 0 or 1;

W² is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)C(O)N(R⁸)—, —N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—,—CH(R⁷)N(C(O)OR⁸)—, —CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—,—CH(R⁷)C(O)N(R⁸)—, —CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or—CH(R⁷)N(R⁸)S(O)₂—;

R² is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,bicyclic aryl, substituted monocyclic aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkyl C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₁₋₁₀alkyl-C₂₋₁₀alkenyl, C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₂₋₁₀alkyl-monocyclicaryl, monocyclic aryl-C₂₋₁₀alkyl, C₁₋₁₀alkylbicycloaryl,bicycloaryl-C₁₋₁₀alkyl, substituted C₁₋₁₀alkylaryl, substitutedaryl-C₁₋₁₀alkyl, C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₂₋₁₀alkenyl-C₁₋₁₀alkyl,C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl, C₂₋₁₀alkenylhetaryl,C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl,C₂₋₁₀alkynylheteroalkyl, C₂₋₁₀alkynylheterocylyl,C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxy C₁₋₁₀alkyl,C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl, heterocyclyl,heteroalkyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,aryl-heterocyclyl, or hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl,hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl, hetaryl-heteroalkyl, orhetaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroarylmoiety is unsubstituted, or wherein each of bicyclic aryl, heteroarylmoiety or monocyclic aryl moiety is substituted with one or moreindependent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₂R³¹,—SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

R³ and R⁴ are independently hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³², aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkylC₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₁₋₁₀alkyl-C₂₋₁₀alkenyl, C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl,C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl,heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl,heteroalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein eachof said aryl or heteroaryl moiety is unsubstituted or is substitutedwith one or more independent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵,—NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

R⁵ is hydrogen;

each of R³¹, R³², and R³³ is independently H or C₁₋₁₀alkyl, wherein theC₁₋₁₀alkyl is unsubstituted or is substituted with one or more aryl,heteroalkyl, heterocyclyl, or hetaryl group, wherein each of said aryl,heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or issubstituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃, —O-aryl,—OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl),—NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl), —C(O)(C₁₋₁₀alkyl-aryl),—C(O)(aryl), —CO₂—C₁₋₁₀alkyl, —CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl,—C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵,—C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl), —O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂,—CN, —S(O)₀₋₂C₁₋₁₀alkyl, —S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂ aryl,—SO₂N(aryl), —SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or—SO₂NR³⁴R³⁵;

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen atom;

-   each of R⁷ and R⁸ is independently hydrogen, C₁₋₁₀alkyl,    C₂₋₁₀alkenyl, aryl, heteroaryl, heterocyclyl or C₃₋₁₀cycloalkyl,    each of which except for hydrogen is unsubstituted or is substituted    by one or more independent R⁶; and

R⁶ is halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, eachof which is unsubstituted or is substituted with one or more independenthalo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², or—NR³⁴R³⁵; and

M₁ of Formula B and M₁ of Formula C are the same; R₁ of Formula A and R₁of Formula C are the same; R₃₁ of Formula A and R₃₁ of Formula C are thesame; R₃₂ of Formula A and R₃₂ of Formula C are the same; X₁ of FormulaA and X₁ of Formula C are the same; X₂ of Formula A and X₂ of Formula Care the same; and X₃ of Formula A and X₃ of Formula C are the same.

In some embodiments of the process for synthesizing a compound ofFormula C, T₁ is iodo or bromo.

In other embodiments of the process for synthesizing a compound ofFormula C, the compound of Formula B is a compound having one of thefollowing formulae:

In some embodiments of the process for synthesizing a compound ofFormula C, each of the compound of Formula B and the compound of FormulaC is the compound wherein:

X₁ and X₂ are N;

R₁ is -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkylheterocylyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³ substituents;

R³ is hydrogen, —OH, —OR³¹, —NR³¹R³², —C(O)R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, orheterocyclyl, wherein each of said aryl or heteroaryl moiety isunsubstituted or is substituted with one or more independent alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³², and wherein each of saidalkyl, cycloalkyl, or heterocyclyl moiety is unsubstituted or issubstituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²; andwherein -(W²)_(k) is —NR⁷—, —N(R⁷)C(O)— or —N(R⁷)S(O)₂—.

In some embodiments, the compound of Formula A reacts with the compoundof Formula B in the presence of palladium tetrakis (triphenylphosphine).In some embodiments, when the compound of Formula A reacts with thecompound of Formula B in the presence of palladium tetrakis(triphenylphosphine), the palladium tetrakis (triphenylphosphine) ispresent in an amount from about 0.07 molar equivalents to about 0.15molar equivalents of the compound of Formula A.

In another aspect, the invention provides a composition comprising acompound of Formula A and a compound of Formula B:

or a salt thereof, wherein: T is halo; X₁ is N or C-E¹, X₂ is N, and X₃is C; or X₁ is N or C-E¹, X₂ is C, and X₃ is N; wherein no more than tworing nitrogen atoms of the compound of Formula A are adjacent; andwherein no more than two ring nitrogen atoms of the compound of FormulaC are adjacent;

each of G is independently H or R_(G1); and R_(G1) is alkyl, alkenyl, oraryl;

or the G groups of

join together to form a 5- or 6-membered cyclic moiety;

M of Formula B is a M₁ moiety, and wherein M₁ of Formula B has one ofthe following structures:

E¹ is -(W¹)_(j)-R⁴ wherein j is 0 or 1;

W¹ is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—, —CH(R⁷)N(C(O)OR⁸)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—;

k is 0 or 1;

W² is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)C(O)N(R⁸)—, —N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—,—CH(R⁷)N(C(O)OR⁸)—, —CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—,—CH(R⁷)C(O)N(R⁸)—, —CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, orCH(R⁷)N(R⁸)S(O)₂—;

R₁ is hydrogen, -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl,-L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl, -L-aryl, -L-heteroaryl, -L-C₁₋₁₀alkylaryl,-L-C₁₋₁₀alkylhetaryl, -L-C₁₋₁₀alkylheterocylyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₂₋₁₀alkenyl-C₃-cycloalkyl,-L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl, -L-heteroalkyl, -L-heteroalkylaryl,-L-heteroalkylheteroaryl, -L-heteroalkyl-heterocylyl,-L-heteroalkyl-C₃₋₈cycloalkyl, -L-aralkyl, -L-heteroaralkyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

R² is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,bicyclic aryl, substituted monocyclic aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₁₋₁₀alkyl-C₂₋₁₀alkenyl, C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₂₋₁₀alkyl-monocyclicaryl, monocyclic aryl-C₂₋₁₀alkyl, C₁₋₁₀alkylbicycloaryl,bicycloaryl-C₁₋₁₀alkyl, substituted C₁₋₁₀alkylaryl, substitutedaryl-C₁₋₁₀alkyl, C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₂₋₁₀alkenyl-C₁₋₁₀alkyl,C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl, C₂₋₁₀alkenylhetaryl,C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl,C₂₋₁₀alkynylheteroalkyl, C₂₋₁₀alkynylheterocylyl,C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxy C₁₋₁₀alkyl,C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl, heterocyclyl,heteroalkyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,aryl-heterocyclyl, or hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl,hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl, hetaryl-heteroalkyl, orhetaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroarylmoiety is unsubstituted, or wherein each of bicyclic aryl, heteroarylmoiety or monocyclic aryl moiety is substituted with one or moreindependent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₂R³¹,—SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

R³ and R⁴ are independently hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³², aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkylC₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₁₋₁₀alkyl-C₂₋₁₀alkenyl, C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl,C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl,heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl,heteroalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein eachof said aryl or heteroaryl moiety is unsubstituted or is substitutedwith one or more independent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵,—NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

R⁵ is hydrogen;

each of R⁷ and R⁸ is independently hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,aryl, heteroaryl, heterocyclyl or C₃₋₁₀cycloalkyl, each of which exceptfor hydrogen is unsubstituted or is substituted by one or moreindependent R⁶;

R⁶ is halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, eachof which is unsubstituted or is substituted with one or more independenthalo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², orNR³⁴R³⁵;

each of R³¹, R³², and R³³ is independently H or C₁₋₁₀alkyl, wherein theC₁₋₁₀alkyl is unsubstituted or is substituted with one or more aryl,heteroalkyl, heterocyclyl, or hetaryl group, wherein each of said alkyl,aryl, heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or issubstituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃, —O-aryl,—OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl),—NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl), —C(O)(C₁₋₁₀alkyl-aryl),—C(O)(aryl), —CO₂—C₁₋₁₀alkyl, —CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl,—C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵,—C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl), —O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂,—CN, —S(O)₀₋₂C₁₋₁₀alkyl, —S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₂ aryl,—SO₂N(aryl), —SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or—SO₂NR³⁴R³⁵; and

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen atom.

In some embodiments of the compositions of the invention, each of thecompound of Formula A and the compound of Formula B is the compoundwherein:

X₁ and X₂ are N; R₁ is -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl,-L-C₁₋₁₀alkylheterocylyl, or -L-heterocyclyl, each of which isunsubstituted or is substituted by one or more independent R³substituents; R³ is hydrogen, —OH, —OR³¹, —NR³¹R³², —C(O)R³¹,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl,or heterocyclyl, wherein each of said aryl or heteroaryl moiety isunsubstituted or is substituted with one or more independent alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³², and wherein each of saidalkyl, cycloalkyl, or heterocyclyl moiety is unsubstituted or issubstituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²; andwherein -(W²)_(k)- is —NR⁷—, —N(R⁷)C(O)— or —N(R⁷)S(O)₂—.

In some embodiments of the compositions of the invention, thecomposition further comprises a compound of

or a salt thereof, wherein:

M₁ of Formula B and M₁ of Formula C are the same; R₁ of Formula A and R₁of Formula C are the same; R₃₁ of Formula A and R₃₁ of Formula C are thesame; R₃₂ of Formula A and R₃₂ of Formula C are the same; X₁ of FormulaA and X₁ of Formula C are the same; X₂ of Formula A and X₂ of Formula Care the same; and X₃ of Formula A and X₃ of Formula C are the same.

In some embodiments of the compositions of the invention, thecomposition further comprises an organic solvent.

In another aspect, the invention provides a process for synthesizing acompound of Formula G-6-B:

comprising the step of allowing a compound of Formula G-6 to react withan acid under conditions effective for synthesizing a compound ofFormula G-6-B.

In some embodiments of the process for synthesizing a compound ofFormula G-6-B, the acid is hydrochloric acid.

In another aspect, the invention provides a process for synthesizing acompound of Formula G-6:

comprising the step of allowing a compound of Formula 1-2 to react withbis(pinacolato)diboron under conditions effective for synthesis of thecompound of Formula G-6.

In yet another aspect, the invention provides a process for synthesizinga compound of Formula 1-2:

comprising the step of allowing a compound of Formula 1-1 to react witha cyanogen halide under conditions effective to synthesize the compoundof Formula 1-2.

In some embodiments of the process for synthesizing a compound ofFormula 1-2, the cyanogen halide is cyanogen bromide.

In a further aspect, the invention provides a process for synthesizing acompound of Formula B:

comprising the step of allowing a compound of Formula D to react with abase and a trialkyl borate under conditions effective to synthesize acompound of Formula B; wherein: G is alkyl; T₂ is halo, triflate,tosylate or mesylate; each of M of Formula D and M of Formula B is a M₁moiety, and wherein M₁ moiety of Formula D and M₁ moiety of Formula Bare identical, having one of the following structures:

R⁵ is hydrogen; k is 1; -W²-R is —NH-G_(p);

G_(p) is acetyl, tert-butyl carbamate (Boc), carbobenzyloxy (Cbz),benzyl (Bz), fluorenylmethyloxycarbonyl (FMOC), or p-methoxybenzyl(PMB); and wherein G_(p) of Formula D and G_(p) of Formula B are thesame.

In other embodiments of the process for synthesizing a compound ofFormula B, the base is n-butyllithium. In yet other embodiments, thetrialkyl borate is triisopropyl borate. In some embodiments of theprocess for synthesizing a compound of Formula B, each of the compoundof Formula D and the compound of Formula B is the compound wherein-(W²)_(k)- is —NR⁷—, —N(R⁷)C(O)— or —N(R⁷)S(O)₂—.

In some embodiments, the process further comprises the step of allowingthe compound of Formula B wherein -W²-R² is —NH-G_(p) and G_(p) istert-butyl carbamate to react with a reagent under conditions effectiveto yield a compound of Formula B, wherein -W²-R² is —NH₂. In someembodiments, the reagent is hydrochloric acid.

In yet another aspect, the invention provides a process for synthesizinga compound of Formula 3-4:

comprising the step of allowing a compound of Formula 3-3 to react witha cyanogen halide under conditions effective for synthesizing a compoundof Formula 3-4; wherein:

X₁ is N or C-E¹, X₂ is N, and X₃ is C; or X₁ is N or C-E¹, X₂ is C, andX₃ is N; wherein no more than two ring nitrogen atoms of the compound ofFormula 3-3 are adjacent; and wherein no more than two ring nitrogenatoms of the compound of Formula 3-4 are adjacent;

E¹ is -(W¹)_(j)-R⁴ wherein j is 0 or 1;

W¹ is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)S(O)—, —N(R⁷)S(O)₂, —C(O)O—, —CH(R⁷)N(C(O)OR⁸)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—;

R₁ is hydrogen, -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl,-L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl, -L-aryl, -L-heteroaryl, -L-C₁₋₁₀alkylaryl,-L-C₁₋₁₀alkylhetaryl, -L-C₁₋₁₀alkylheterocylyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₂₋₁₀alkenyl-C₃₋₈cycloalkyl,-L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl, -L-heteroalkyl, -L-heteroalkylaryl,-L-heteroalkylheteroaryl, -L-heteroalkyl-heterocylyl,-L-heteroalkyl-C₃₋₈cycloalkyl, -L-aralkyl, -L-heteroaralkyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

R³ and R⁴ are independently hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³², aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkylC₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₁₋₁₀alkyl-C₂₋₁₀alkenyl, C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl,C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl,heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, hetaryl C₂₋₁₀alkynyl, hetaryl C₃₋₈cycloalkyl,heteroalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein eachof said aryl or heteroaryl moiety is unsubstituted or is substitutedwith one or more independent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵,—NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

each of R³¹, R³², and R³³ is independently H or C₁₋₁₀alkyl, wherein theC₁₋₁₀alkyl is unsubstituted or is substituted with one or more aryl,heteroalkyl, heterocyclyl, or hetaryl group, wherein each of said alkyl,aryl, heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or issubstituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃, —O-aryl,—OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl),—NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl), —C(O)(C₁₋₁₀alkyl-aryl),—C(O)(aryl), —CO₂—C₁₋₁₀alkyl, —CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl,—C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵,C(═O)NH₂, —OCF₃, O(C₁₋₁₀alkyl), —O-aryl, N(aryl)(C₁₋₁₀alkyl), —NO₂, —CN,—S(O)₀₋₂C₁₋₁₀alkyl, —S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂ aryl, —SO₂N(aryl),—SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or —SO₂NR³⁴R³⁵;

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen atom;

-   each of R⁷ and R⁸ is independently hydrogen, C₁₋₁₀alkyl,    C₂₋₁₀alkenyl, aryl, heteroaryl, heterocyclyl or C₃₋₁₀cycloalkyl,    each of which except for hydrogen is unsubstituted or is substituted    by one or more independent R⁶; and

R⁶ is halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, eachof which is unsubstituted or is substituted with one or more independenthalo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², or—NR³⁴R³⁵; and

wherein R₁ of Formula 3-3 and R₁ of Formula 3-4 are the same; R₃₁ ofFormula 3-3 and R₃₁ of Formula 3-4 are the same; R₃₂ of Formula 3-3 andR₃₂ of Formula 3-4 are the same; X₁ of Formula 3-3 and X₁ of Formula 3-4are the same; X₂ of Formula 3-3 and X₂ of Formula 3-4 are the same; andX₃ of Formula 3-3 and X₃ of Formula 3-4 are the same.

In some embodiments of the process of the invention, each of thecompound of Formula 3-3 and the compound of Formula 3-4 is the compoundwherein:

X₁ and X₂ are N;

R₁ is -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkylheterocylyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³ substituents; and wherein

R³ is hydrogen, —OH, —OR³¹, —NR³¹R³², —C(O)R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, orheterocyclyl, wherein each of said aryl or heteroaryl moiety isunsubstituted or is substituted with one or more independent alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³², and wherein each of saidalkyl, cycloalkyl, or heterocyclyl moiety is unsubstituted or issubstituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³².

In some embodiments for synthesizing a compound of Formula 3-4, thecyanogen halide is cyanogen bromide.

In another aspect, the invention provides a process for synthesizing acompound of Formula 3-3:

comprising the step of allowing a compound of Formula 3-2 to react witha reagent under conditions effective to synthesize a compound of Formula3-3; wherein;

X₁ is N or C-E¹, X₂ is N, and X₃ is C; or X₁ is N or C-E¹, X₂ is C, andX₃ is N; wherein no more than two ring nitrogen atoms of the compound ofFormula 3-3 are adjacent; and wherein no more than two ring nitrogenatoms of the compound of Formula 3-4 are adjacent;

E¹ is -(W¹)_(j)-R⁴ wherein j is 0 or 1;

W¹ is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—, —CH(R⁷)N(C(O)OR)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—;

R₁ is hydrogen, -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl,-L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl, -L-aryl, -L-heteroaryl, -L-C₁₋₁₀alkylaryl,-L-C₁₋₁₀alkylhetaryl, -L-C₁₋₁₀alkylheterocylyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₂₋₁₀alkenyl-C₃₋₈cycloalkyl,-L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl, -L-heteroalkyl, -L-heteroalkylaryl,-L-heteroalkylheteroaryl, -L-heteroalkyl-heterocylyl,-L-heteroalkyl-C₃₋₈cycloalkyl, -L-aralkyl, -L-heteroaralkyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

R³ and R⁴ are independently hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³², aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkylC₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₁₋₁₀alkyl-C₂₋₁₀alkenyl, C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl,C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl,heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl,heteroalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein eachof said aryl or heteroaryl moiety is unsubstituted or is substitutedwith one or more independent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵,—NO₂, —CN, —S(O)₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹R³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

each of R³¹, R³², and R³³ is independently H or C₁₋₁₀alkyl, wherein theC₁₋₁₀alkyl is unsubstituted or is substituted with one or more aryl,heteroalkyl, heterocyclyl, or hetaryl group, wherein each of said alkyl,aryl, heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or issubstituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃, —O-aryl,—OCF₃, —OC₁alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl),—NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl), —C(O)(C₁₋₁₀alkyl-aryl),—C(O)(aryl), —CO₂—C₁₋₁₀alkyl, —CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl,—C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵,—C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl), —O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂,—CN, —S(O)₀₋₂C₁₋₁₀alkyl, —S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂aryl,—SO₂N(aryl), —SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or—SO₂NR³⁴R³⁵;

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen atom;

-   each of R⁷ and R⁸ is independently hydrogen, C₁₋₁₀alkyl,    C₂₋₁₀alkenyl, aryl, heteroaryl, heterocyclyl or C₃₋₁₀cycloalkyl,    each of which except for hydrogen is unsubstituted or is substituted    by one or more independent R⁶; and

R⁶ is halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, CN, S(O)₀₋₂C₁₋₁₀alkyl, S(O)₀₋₂aryl,—SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, eachof which is unsubstituted or is substituted with one or more independenthalo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², or—NR³⁴R³⁵; and

wherein R₁ of Formula 3-2 and R₁ of Formula 3-3 are the same; R₃₁ ofFormula 3-2 and R₃₁ of Formula 3-3 are the same; R₃₂ of Formula 3-2 andR₃₂ of Formula 3-3 are the same; X₁ of Formula 3-2 and X₁ of Formula 3-3are the same; X₂ of Formula 3-2 and X₂ of Formula 3-3 are the same; andX₃ of Formula 3-2 and X₃ of Formula 3-3 are the same.

In some embodiments of the process for synthesizing a compound ofFormula 3-3, the reagent is (a) sodium dithionite or (b) palladium oncarbon in the presence of hydrogen gas.

In some embodiments of the process for synthesizing a compound ofFormula 3-3, each of the compound of Formula 3-2 and the compound ofFormula 3-3 is a compound wherein: X₁ and X₂ are N; R₁ is -L-C₁₋₁₀alkyl,-L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkylheterocylyl, or -L-heterocyclyl, each ofwhich is unsubstituted or is substituted by one or more independent R³substituents; and wherein

R³ is hydrogen, —OH, —OR³¹, —NR³¹R³², —C(O)R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, orheterocyclyl, wherein each of said aryl or heteroaryl moiety isunsubstituted or is substituted with one or more independent alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³², and wherein each of saidalkyl, cycloalkyl, or heterocyclyl moiety is unsubstituted or issubstituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³².

In another aspect, the invention provides a process for synthesizing acompound of Formula 3-2:

comprising the step of allowing a compound of Formula 3-1 to react witha reagent under conditions effective to synthesize the compound ofFormula 3-2; wherein:

X₁ is N or C-E¹, X₂ is N, and X₃ is C; or X₁ is N or C-E¹, X₂ is C, andX₃ is N; wherein no more than two ring nitrogen atoms of the compound ofFormula 3-1 are adjacent; and wherein no more than two ring nitrogenatoms of the compound of Formula 3-2 are adjacent;

E¹ is -(W¹)_(j)-R⁴ wherein j is 0 or 1;

W¹ is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—, —CH(R⁷)N(C(O)OR)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—;

R₁ is hydrogen, -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl,-L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl, -L-aryl, -L-heteroaryl, -L-C₁₋₁₀alkylaryl,-L-C₁₋₁₀alkylhetaryl, -L-C₁₋₁₀alkylheterocylyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₂₋₁₀alkenyl-C₃₋₈cycloalkyl,-L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl, -L-heteroalkyl, -L-heteroalkylaryl,-L-heteroalkylheteroaryl, -L-heteroalkyl-heterocylyl,-L-heteroalkyl-C₃₋₈cycloalkyl, -L-aralkyl, -L-heteroaralkyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

R³ and R⁴ are independently hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³², aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkylC₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₁₋₁₀alkyl-C₂₋₁₀alkenyl, C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl,C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl,heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl,heteroalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein eachof said aryl or heteroaryl moiety is unsubstituted or is substitutedwith one or more independent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵,—NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

each of R³¹, R³², and R³³ is independently H or C₁₋₁₀alkyl, wherein theC₁₋₁₀alkyl is unsubstituted or is substituted with one or more aryl,heteroalkyl, heterocyclyl, or hetaryl group, wherein each of said alkyl,aryl, heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or issubstituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃, —O-aryl,—OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl),—NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl), —C(O)(C₁₋₁₀alkyl-aryl),—C(O)(aryl), —CO₂—C₁₋₁₀alkyl, —CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl,—C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵,—C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl), —O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂,—CN, S(O)₀₋₂C₁₋₁₀alkyl, —S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂ aryl,—SO₂N(aryl), —SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or—SO₂NR³⁴R³⁵;

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen atom;

each of R⁷ and R⁸ is independently hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,aryl, heteroaryl, heterocyclyl or C₃₋₁₀cycloalkyl, each of which exceptfor hydrogen is unsubstituted or is substituted by one or moreindependent R⁶; and

R⁶ is halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, S(O)₀₋₂C₁₋₁₀alkyl, S(O)₀₋₂aryl,—SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, eachof which is unsubstituted or is substituted with one or more independenthalo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², or—NR³⁴R³⁵; and

wherein R₁ of Formula 3-1 and R₁ of Formula 3-23 are the same; R₃₁ ofFormula 3-1 and R₃₁ of Formula 3-2 are the same; R₃₂ of Formula 3-1 andR₃₂ of Formula 3-2 are the same; X₁ of Formula 3-1 and X₁ of Formula 3-2are the same; X₂ of Formula 3-1 and X₂ of Formula 3-2 are the same; andX₃ of Formula 3-1 and X₃ of Formula 3-2 are the same.

In some embodiments of the process for synthesizing a compound ofFormula 3-2, the reagent is nitric acid.

In some embodiments of the process for synthesizing a compound ofFormula 3-2, each of the compound of Formula 3-1 and the compound ofFormula 3-2 is a compound wherein:

X₁ and X₂ are N; R₁ is -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl,-L-C₁₋₁₀alkylheterocylyl, or -L-heterocyclyl, each of which isunsubstituted or is substituted by one or more independent R³substituents; and wherein

R³ is hydrogen, —OH, —OR³¹, —NR³¹R³², —C(O)R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, orheterocyclyl, wherein each of said aryl or heteroaryl moiety isunsubstituted or is substituted with one or more independent alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³², and wherein each of saidalkyl, cycloalkyl, or heterocyclyl moiety is unsubstituted or issubstituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³².

The invention also provides a compound of Formula E:

or a salt thereof, wherein:

G is H or R_(G1); and R_(G1) is alkyl, alkenyl, or aryl;

or the G groups of

join together to form a 5- or 6-membered cyclic moiety; and

R_(G2) is H, acetyl, tert-butyl carbamate (Boc), carbobenzyloxy (Cbz),benzyl (Bz), fluorenylmethyloxycarbonyl (FMOC), or p-methoxybenzyl(PMB).

In some embodiments, the compound of Formula E is:

In some embodiments, a compound of the invention is a compound ofFormula F:

or a salt thereof, wherein R_(G2) is H, tert-butyl carbamate, acetyl,tert-butyl carbamate (Boc), carbobenzyloxy (Cbz), benzyl (Bz),fluorenylmethyloxycarbonyl (FMOC), or p-methoxybenzyl (PMB).

In some embodiments, the invention provides a compound of Formula 3-3′:

or a salt thereof wherein:

X₁ is N or C-E¹, X₂ is N, and X₃ is C; or X₁ is N or C-E¹, X₂ is C, andX₃ is N;

wherein no more than two ring nitrogen atoms are adjacent;

E¹ is -(W¹)_(j)-R⁴ wherein j is 0 or 1;

W¹ is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)S(O)—, —N(R⁷)S(O)₂, —C(O)O—, —CH(R⁷)N(C(O)OR⁸)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—;

R₁ is hydrogen, -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl,-L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl, -L-aryl, -L-heteroaryl, -L-C₁₋₁₀alkylaryl,-L-C₁₋₁₀alkylhetaryl, -L-C₁₋₁₀alkylheterocylyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₂₋₁₀alkenyl-C₃₋₈cycloalkyl,-L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl, -L-heteroalkyl, -L-heteroalkylaryl,-L-heteroalkylheteroaryl, -L-heteroalkyl-heterocylyl,-L-heteroalkyl-C₃₋₈cycloalkyl, -L-aralkyl, -L-heteroaralkyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

R³ and R⁴ are independently hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³², aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₁₋₁₀alkyl-C₂₋₁₀alkenyl, C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl,C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl,heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, hetaryl C₂₋₁₀alkynyl, hetaryl C₃₋₈cycloalkyl,heteroalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein eachof said aryl or heteroaryl moiety is unsubstituted or is substitutedwith one or more independent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, CO₂R³¹, —C(═O)NR³¹R³², C(═O)NR³⁴R³⁵, —NO₂,—CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³² and wherein each of said alkyl, cycloalkyl, heterocyclyl,or heteroalkyl moiety is unsubstituted or is substituted with one ormore halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³², —NR³⁴R³⁵,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

each of R³¹, R³², and R³³ is independently H or C₁₋₁₀alkyl, wherein theC₁₋₁₀alkyl is unsubstituted or is substituted with one or more aryl,heteroalkyl, heterocyclyl, or hetaryl group, wherein each of said aryl,heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or issubstituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃, —O-aryl,—OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl),—NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl), —C(O)(C₁₋₁₀alkyl-aryl),—C(O)(aryl), —CO₂—C₁₋₁₀alkyl, —CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl,—C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵,C(═O)NH₂, —OCF₃, O(C₁₋₁₀alkyl), —O-aryl, N(aryl)(C₁₋₁₀alkyl), —NO₂, —CN,—S(O)₀₋₂C₁₋₁₀alkyl, —S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂aryl, —SO₂N(aryl),—SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or —SO₂NR³⁴R³⁵;

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen atom;

-   each of R⁷ and R⁸ is independently hydrogen, C₁₋₁₀alkyl,    C₂₋₁₀alkenyl, aryl, heteroaryl, heterocyclyl or C₃₋₁₀cycloalkyl,    each of which except for hydrogen is unsubstituted or is substituted    by one or more independent R⁶;

R⁶ is halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, eachof which is unsubstituted or is substituted with one or more independenthalo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², or—NR³⁴R³⁵; and

R³⁶ is NH₂ or NO₂.

In some embodiments, the compound of Formula 3-3′ is the compoundwherein:

X₁ and X₂ are N;

R₁ is -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkylheterocylyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³ substituents;

R³ is hydrogen, —OH, —OR³¹, —NR³¹R³², —C(O)R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, orheterocyclyl, wherein each of said aryl or heteroaryl moiety isunsubstituted or is substituted with one or more independent alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³², and wherein each of saidalkyl, cycloalkyl, or heterocyclyl moiety is unsubstituted or issubstituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²; andwherein -(W²)_(k)- is —NR⁷—, —N(R⁷)C(O)— or N(R⁷)S(O)₂—.

In another aspect, the invention provides a composition comprising acompound of Formula 3-3:

or a salt thereof, and a cyanogen halide wherein:

X₁ is N or C-E¹, X₂ is N, and X₃ is C; or X₁ is N or C-E¹, X₂ is C, andX₃ is N;

wherein no more than two nitrogen ring atoms are adjacent;

E¹ is -(W¹)_(j)-R⁴ wherein j is 0 or 1;

W¹ is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)S(O)—, —N(R⁷)S(O)₂, —C(O)O—, —CH(R⁷)N(C(O)OR⁸)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—;

R₁ is hydrogen, -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl,-L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl, -L-aryl, -L-heteroaryl, -L-C₁₋₁₀alkylaryl,-L-C₁₋₁₀alkylhetaryl, -L-C₁₋₁₀alkylheterocylyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₂₋₁₀alkenyl-C₃₋₈cycloalkyl,-L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl, -L-heteroalkyl, -L-heteroalkylaryl,-L-heteroalkylheteroaryl, -L-heteroalkyl-heterocylyl,-L-heteroalkyl-C₃₋₈cycloalkyl, -L-aralkyl, -L-heteroaralkyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

R³ and R⁴ are independently hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³², aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkylC₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₁₋₁₀alkyl-C₂₋₁₀alkenyl, C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl,C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl,heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, hetaryl C₂₋₁₀alkynyl, hetaryl C₃₋₈cycloalkyl,heteroalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein eachof said aryl or heteroaryl moiety is unsubstituted or is substitutedwith one or more independent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵,—NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, NR³¹S(O)(O)₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, C(═O)NR³⁴R³⁵, or C(═O)NR³¹R³²;

each of R⁷ and R⁸ is independently hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,aryl, heteroaryl, heterocyclyl or C₃₋₁₀cycloalkyl, each of which exceptfor hydrogen is unsubstituted or is substituted by one or moreindependent R⁶;

R⁶ is halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, eachof which is unsubstituted or is substituted with one or more independenthalo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, SO₂NR³¹R³², —NR³¹R³², or—NR³⁴R³⁵;

each of R³¹, R³², and R³³ is independently H or C₁₋₁₀alkyl, wherein theC₁₋₁₀alkyl is unsubstituted or is substituted with one or more aryl,heteroalkyl, heterocyclyl, or hetaryl group, wherein each of said aryl,heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or issubstituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃, —O-aryl,—OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl),—NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl), —C(O)(C₁₋₁₀alkyl-aryl),—C(O)(aryl), —CO₂—C₁₋₁₀alkyl, —CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl,—C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵,—C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl), —O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂,—CN, —S(O)₀₋₂C₁₋₁₀alkyl, —S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂aryl,—SO₂N(aryl), —SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or—SO₂NR³⁴R³⁵; and

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen atom.

In some embodiments of the composition comprising a compound of Formula3-3 and cyanogen halide, the cyanogen halide is cyanogen bromide.

In some embodiments of the composition comprising a compound of Formula3-3 and cyanogen halide, the compound of Formula 3-3 is the compoundwherein:

X₁ and X₂ are N;

R₁ is -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkylheterocylyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³ substituents; and wherein

R³ is hydrogen, —OH, —OR³¹, —NR³¹R³², —C(O)R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, orheterocyclyl, wherein each of said aryl or heteroaryl moiety isunsubstituted or is substituted with one or more independent alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃,OR, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵,—NO₂, —CN, —S(O)₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³²NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl, orheterocyclyl moiety is unsubstituted or is substituted with one or morealkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃,—OCF₃, —OR³¹, —O-aryl, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³².

In some embodiments of the composition comprising a compound of Formula3-3 and cyanogen halide, the composition further comprises a compound ofFormula 3-4:

or a salt thereof, wherein: R₁ of Formula 3-3 and R₁ of Formula 3-4 arethe same; R₃₁ of Formula 3-3 and R₃₁ of Formula 3-4 are the same; R₃₂ ofFormula 3-3 and R₃₂ of Formula 3-4 are the same; X₁ of Formula 3-3 andX₁ of Formula 3-4 are the same; X₂ of Formula 3-3 and X₂ of Formula 3-4are the same; and X₃ of Formula 3-3 and X₃ of Formula 3-4 are the same.

In another aspect, the invention provides a composition comprising acompound of Formula 3-1:

or a salt thereof, and a nitrating reagent wherein:

X₁ is N or C-E¹, X₂ is N, and X₃ is C; or X₁ is N or C-E¹, X₂ is C, andX₃ is N;

wherein no more than two nitrogen ring atoms are adjacent;

E¹ is -(W¹)_(j)-R⁴ wherein j is 0 or 1;

W¹ is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—, —CH(R⁷)N(C(O)OR)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—;

R₁ is hydrogen, -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl,-L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl, -L-aryl, -L-heteroaryl, -L-C₁₋₁₀alkylaryl,-L-C₁₋₁₀alkylhetaryl, -L-C₁₋₁₀alkylheterocylyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₂₋₁₀alkenyl-C₃₋₈cycloalkyl,-L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl, -L-heteroalkyl, -L-heteroalkylaryl,-L-heteroalkylheteroaryl, -L-heteroalkyl-heterocylyl,-L-heteroalkyl-C₃₋₈cycloalkyl, -L-aralkyl, -L-heteroaralkyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

R³ and R⁴ are independently hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³², aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkylC₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₁₋₁₀alkyl-C₂₋₁₀alkenyl, C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl,C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl,heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl,heteroalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein eachof said aryl or heteroaryl moiety is unsubstituted or is substitutedwith one or more independent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵,—NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

each of R⁷ and R⁸ is independently hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,aryl, heteroaryl, heterocyclyl or C₃₋₁₀cycloalkyl, each of which exceptfor hydrogen is unsubstituted or is substituted by one or moreindependent R⁶;

R⁶ is halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, eachof which is unsubstituted or is substituted with one or more independenthalo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², orNR³⁴R³⁵;

each of R³¹, R³², and R³³ is independently H or C₁₋₁₀alkyl, wherein theC₁₋₁₀alkyl is unsubstituted or is substituted with one or more aryl,heteroalkyl, heterocyclyl, or hetaryl group, wherein each of said aryl,heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or issubstituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃, —O-aryl,—OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl),—NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl), —C(O)(C₁₋₁₀alkyl-aryl),—C(O)(aryl), —CO₂—C₁₋₁₀alkyl, —CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl,—C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵,—C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl), —O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂,—CN, —S(O)₂C₁₋₁₀alkyl, S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂aryl, —SO₂N(aryl),—SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or —SO₂NR³⁴R³⁵; and

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen atom.

In some embodiments of the composition comprising a compound of Formula3-1 and a nitrating agent, the compound of Formula 3-1 is the compoundwherein:

X₁ and X₂ are N;

R₁ is -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkylheterocylyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³ substituents;

R³ is hydrogen, —OH, —OR³¹, —NR³¹R³², —C(O)R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, orheterocyclyl, wherein each of said aryl or heteroaryl moiety isunsubstituted or is substituted with one or more independent alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³², and wherein each of saidalkyl, cycloalkyl, or heterocyclyl moiety is unsubstituted or issubstituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²; andwherein -(W²)_(k)- is —NR⁷—, —N(R⁷)C(O)— or —N(R⁷)S(O)₂—.

In some embodiments, the nitrating agent is nitric acid.

In some embodiments of the composition comprising a compound of Formula3-1 and a nitrating agent, the composition further comprises a compoundof Formula 3-2:

or a salt thereof, wherein:

R₁ of Formula 3-1 and R₁ of Formula 3-2 are the same; R₃₁ of Formula 3-1and R₃₁ of Formula 3-2 are the same; R₃₂ of Formula 3-1 and R₃₂ ofFormula 3-2 are the same; X₁ of Formula 3-1 and X₁ of Formula 3-2 arethe same; X₂ of Formula 3-1 and X₂ of Formula 3-2 are the same, and X₃of Formula 3-1 and X₃ of Formula 3-2 are the same.

In another aspect, the invention provides a process for synthesizing acompound of Formula C:

comprising the step of allowing a compound of Formula A to react with acompound of Formula B under conditions that are effective forsynthesizing a compound of Formula C; wherein;

T₁ is halo;

X₁ is N or C-E¹, X₂ is N, and X₃ is C; or X₁ is N or C-E¹, X₂ is C, andX₃ is N; wherein no more than two ring nitrogen atoms of the compound ofFormula A are adjacent; and wherein no more than two ring nitrogen atomsof the compound of Formula C are adjacent;

R₁ is hydrogen, -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl,-L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl, -L-aryl, -L-heteroaryl, -L-C₁₋₁₀alkylaryl,-L-C₁₋₁₀alkylhetaryl, -L-C₁₋₁₀alkylheterocylyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₂₋₁₀alkenyl-C₃₋₈cycloalkyl,-L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl, -L-heteroalkyl, -L-heteroalkylaryl,-L-heteroalkylheteroaryl, -L-heteroalkyl-heterocylyl,-L-heteroalkyl-C₃₋₈cycloalkyl, -L-aralkyl, -L-heteroaralkyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

each of G is independently H or R_(G1); and R_(G1) is alkyl, alkenyl, oraryl;

or the G groups of

join together to form a 5- or 6-membered cyclic moiety;

M of Formula B is a M₁ moiety, and wherein M₁ moiety of Formula B and M₁moiety of Formula C are identical, having one of the followingstructures:

E¹ is -(W¹)_(j)-R⁴ wherein j is 0 or 1;

W¹ is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—, —CH(R⁷)N(C(O)OR)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)—;

k is 0 or 1;

W² is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)C(O)N(R⁸)—, —N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—, —CH(R⁷)N(C(O)OR)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(RB)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—;

R² is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,bicyclic aryl, substituted monocyclic aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₁₋₁₀alkyl-C₂₋₁₀alkenyl, C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₂₋₁₀alkyl-monocyclicaryl, monocyclic aryl-C₂₋₁₀alkyl, C₁₋₁₀alkylbicycloaryl,bicycloaryl-C₁₋₁₀alkyl, substituted C₁₋₁₀alkylaryl, substitutedaryl-C₁₋₁₀alkyl, C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₂₋₁₀alkenyl-C₁₋₁₀alkyl,C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl, C₂₋₁₀alkenylhetaryl,C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl,C₂₋₁₀alkynylheteroalkyl, C₂₋₁₀alkynylheterocylyl,C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxy C₁₋₁₀alkyl,C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl, heterocyclyl,heteroalkyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,aryl-heterocyclyl, or hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl,hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl, hetaryl-heteroalkyl, orhetaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroarylmoiety is unsubstituted, or wherein each of bicyclic aryl, heteroarylmoiety or monocyclic aryl moiety is substituted with one or moreindependent halo, —OH, —R³¹, —CF₃, OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₂R³¹,—SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

R³ and R⁴ are independently hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³², aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkylC₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₁₋₁₀alkyl-C₂₋₁₀alkenyl, C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl,C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl,heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl,heteroalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein eachof said aryl or heteroaryl moiety is unsubstituted or is substitutedwith one or more independent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵,—NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

R⁵ is halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹,—SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³²;

each of R³¹, R³², and R³³ is independently H or C₁₋₁₀alkyl, wherein theC₁₋₁₀alkyl is unsubstituted or is substituted with one or more aryl,heteroalkyl, heterocyclyl, or hetaryl group, wherein each of said aryl,heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or issubstituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃, —O-aryl,—OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl),—NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl), —C(O)(C₁₋₁₀alkyl-aryl),—C(O)(aryl), —CO₂—C₁₋₁₀alkyl, —CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl,—C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵,—C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl), —O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂,—CN, —S(O)₀₋₂C₁₋₁₀alkyl, S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂ aryl,—SO₂N(aryl), —SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or—SO₂NR³⁴R³⁵;

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen atom;

-   each of R⁷ and R⁸ is independently hydrogen, C₁₋₁₀alkyl,    C₂₋₁₀alkenyl, aryl, heteroaryl, heterocyclyl or C₃₋₁₀cycloalkyl,    each of which except for hydrogen is unsubstituted or is substituted    by one or more independent R⁶; and

R⁶ is halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, eachof which is unsubstituted or is substituted with one or more independenthalo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², or—NR³⁴R³⁵; and

M₁ of Formula B and M₁ of Formula C are the same; R₅ of Formula B and R₅of Formula C are the same; R₁ of Formula A and R₁ of Formula C are thesame; R₃₁ of Formula A and R₃₁ of Formula C are the same; R₃₂ of FormulaA and R₃₂ of Formula C are the same; X₁ of Formula A and X₁ of Formula Care the same; X₂ of Formula A and X₂ of Formula C are the same; and X₃of Formula A and X₃ of Formula C are the same.

In some of the embodiments of the process for synthesizing a compound ofFormula C, each of the compound of Formula A and the compound of FormulaC is the compound wherein:

X₁ and X₂ are N;

R₁ is -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkylheterocylyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³ substituents;

R³ is hydrogen, —OH, —OR³¹, —NR³¹R³², —C(O)R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, orheterocyclyl, wherein each of said aryl or heteroaryl moiety isunsubstituted or is substituted with one or more independent alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³², and wherein each of saidalkyl, cycloalkyl, or heterocyclyl moiety is unsubstituted or issubstituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²; andwherein

-(W²)_(k)- is —NR⁷—, —N(R⁷)C(O)— or —N(R⁷)S(O)₂—.

In some of the embodiments of the process for synthesizing a compound ofFormula C, the compound of Formula B has one of the followingstructures:

In another aspect, the invention provides a composition comprising acompound of Formula A and a compound of Formula B:

or a salt thereof, wherein:

T is halo;

X₁ is N or C-E¹, X₂ is N, and X₃ is C; or X₁ is N or C-E¹, X₂ is C, andX₃ is N; wherein no more than two ring nitrogen atoms of the compound ofFormula A are adjacent; and wherein no more than two ring nitrogen atomsof the compound of Formula C are adjacent;

each of G is independently H or R_(G1); and R_(G1) is alkyl, alkenyl, oraryl;

or the G groups of

join together to form a 5- or 6-membered cyclic moiety;

M of Formula B is a M₁ moiety, and wherein M₁ moiety of Formula B hasone of the following structures:

E¹ is -(W¹)_(j)-R⁴ wherein j is 0 or 1;

W¹ is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—, —CH(R⁷)N(C(O)OR⁸)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—;

k is 0 or 1;

W² is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)C(O)N(R⁸)—, —N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—,—CH(R⁷)N(C(O)OR⁸)—, —CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—,—CH(R⁷)C(O)N(R⁸)—, —CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or—CH(R⁷)N(R⁸)S(O)₂—;

R₁ is hydrogen, -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl,-L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl, -L-aryl, -L-heteroaryl, -L-C₁₋₁₀alkylaryl,-L-C₁₋₁₀alkylhetaryl, -L-C₁₋₁₀alkylheterocylyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₂₋₁₀alkenyl-C₃₋₈cycloalkyl,-L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl, -L-heteroalkyl, -L-heteroalkylaryl,-L-heteroalkylheteroaryl, -L-heteroalkyl-heterocylyl,-L-heteroalkyl-C₃₋₈cycloalkyl, -L-aralkyl, -L-heteroaralkyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

R² is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,bicyclic aryl, substituted monocyclic aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkyl C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₁₋₁₀alkyl-C₂₋₁₀alkenyl, C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₂₋₁₀alkyl-monocyclicaryl, monocyclic aryl-C₂₋₁₀alkyl, C₁₋₁₀alkylbicycloaryl,bicycloaryl-C₁₋₁₀alkyl, substituted C₁₋₁₀alkylaryl, substitutedaryl-C₁₋₁₀alkyl, C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₂₋₁₀alkenyl-C₁₋₁₀alkyl,C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl, C₂₋₁₀alkenylhetaryl,C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl,C₂₋₁₀alkynylheteroalkyl, C₂₋₁₀alkynylheterocylyl,C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxy C₁₋₁₀alkyl,C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl, heterocyclyl,heteroalkyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,aryl-heterocyclyl, or hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl,hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl, hetaryl-heteroalkyl, orhetaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroarylmoiety is unsubstituted, or wherein each of bicyclic aryl, heteroarylmoiety or monocyclic aryl moiety is substituted with one or moreindependent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₂R³¹,—SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

R³ and R⁴ are independently hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³², aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkylC₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₁₋₁₀alkyl-C₂₋₁₀alkenyl, C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl,C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl,heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl,heteroalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein eachof said aryl or heteroaryl moiety is unsubstituted or is substitutedwith one or more independent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵,—NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³² and wherein each of said alkyl, cycloalkyl, heterocyclyl,or heteroalkyl moiety is unsubstituted or is substituted with one ormore halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³², —NR³⁴R³⁵,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

R⁵ is halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹,—SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³²;

-   each of R⁷ and R⁸ is independently hydrogen, C₁₋₁₀alkyl,    C₂₋₁₀alkenyl, aryl, heteroaryl, heterocyclyl or C₃₋₁₀cycloalkyl,    each of which except for hydrogen is unsubstituted or is substituted    by one or more independent R⁶;

R⁶ is halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, eachof which is unsubstituted or is substituted with one or more independenthalo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², orNR³⁴R³⁵;

each of R³¹, R³², and R³³ is independently H or C₁₋₁₀alkyl, wherein theC₁₋₁₀alkyl is unsubstituted or is substituted with one or more aryl,heteroalkyl, heterocyclyl, or hetaryl group, wherein each of said alkyl,aryl, heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or issubstituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃, —O-aryl,—OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl),—NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl), —C(O)(C₁₋₁₀alkyl-aryl),—C(O)(aryl), —CO₂—C₁₋₁₀alkyl, —CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl,—C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵,—C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl), —O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂,—CN, —S(O)₀₋₂C₁₋₁₀alkyl, —S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂ aryl,—SO₂N(aryl), —SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or—SO₂NR³⁴R³⁵; and

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen atom.

In some embodiments of the composition comprising a compound of FormulaA and a compound of Formula B, the compound of Formula A is the compoundwherein:

X₁ and X₂ are N;

R₁ is -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkylheterocylyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³ substituents;

R³ is hydrogen, —OH, —OR³¹, —NR³¹R³², —C(O)R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, orheterocyclyl, wherein each of said aryl or heteroaryl moiety isunsubstituted or is substituted with one or more independent alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³², and wherein each of saidalkyl, cycloalkyl, or heterocyclyl moiety is unsubstituted or issubstituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²; andwherein -(W²)_(k)- is —NR⁷—, —N(R⁷)C(O)— or —N(R⁷)S(O)₂—.

In some embodiments of the composition comprising a compound of FormulaA and a compound of Formula B, the compound of Formula B is a compoundhaving one of the following formulae:

In some embodiments of the composition comprising a compound of FormulaA and a compound of Formula B, the composition further comprises acompound of Formula C:

or a salt thereof, wherein:

M₁ of Formula B and M₁ of Formula C are the same; R₅ of Formula B and R₅of Formula C are the same; R₁ of Formula A and R₁ of Formula C are thesame; R₁ of Formula A and R₁ of Formula C are the same; R₃₁ of Formula Aand R₃₁ of Formula C are the same; R₃₂ of Formula A and R₃₂ of Formula Care the same; X₁ of Formula A and X₁ of Formula C are the same; X₂ ofFormula A and X₂ of Formula C are the same; and X₃ of Formula A and X₃of Formula C are the same.

In a further aspect the invention provides a compound of Formula I-B:

or a pharmaceutically acceptable salt thereof, wherein:

X₁ is N and X₂ is C₁ or X₁ is C-E¹ and X₂ is C;

R₁ is hydrogen, -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl,-L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl, -L-aryl, -L-heteroaryl, -L-C₁₋₁₀alkylaryl,-L-C₁₋₁₀alkylhetaryl, -L-C₁₋₁₀alkylheterocylyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₂₋₁₀alkenyl-C₃₋₈cycloalkyl,-L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl, -L-heteroalkyl, -L-heteroalkylaryl,-L-heteroalkylheteroaryl, -L-heteroalkyl-heterocylyl,-L-heteroalkyl-C₃₋₈cycloalkyl, -L-aralkyl, -L-heteroaralkyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

M₁ is a moiety having one of the following structures:

k is 0 or 1;

E¹ and E² are independently -(W¹)_(j)-R⁴;

j in E¹ or j in E², is independently 0 or 1;

W¹ is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—, —CH(R⁷)N(C(O)OR⁸)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—;

W² is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,N(R⁷)C(O)N(R⁸)—, —N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—, —CH(R⁷)N(C(O)OR⁸)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—;

R³ and R⁴ are independently hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³², aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₁₋₁₀alkyl-C₂₋₁₀alkenyl, C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl,C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl,heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl,heteroalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein eachof said aryl or heteroaryl moiety is unsubstituted or is substitutedwith one or more independent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵,—NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

R⁵ is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³²;

R² is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²bicyclic aryl, substituted monocyclic aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₁₋₁₀alkyl-C₂₋₁₀alkenyl, C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₂₋₁₀alkyl-monocyclicaryl, monocyclic aryl-C₂₋₁₀alkyl, C₁₋₁₀alkylbicycloaryl,bicycloaryl-C₁₋₁₀alkyl, substituted C₁₋₁₀alkylaryl, substitutedaryl-C₁₋₁₀alkyl, C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₂₋₁₀alkenyl-C₁₋₁₀alkyl,C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl, C₂₋₁₀alkenylhetaryl,C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl,C₂₋₁₀alkynylheteroalkyl, C₂₋₁₀alkynylheterocylyl,C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxy C₁₋₁₀alkyl,C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl, heterocyclyl,heteroalkyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,aryl-heterocyclyl, or hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl,hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl, hetaryl-heteroalkyl, orhetaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroarylmoiety is unsubstituted, or wherein each of bicyclic aryl, heteroarylmoiety or monocyclic aryl moiety is substituted with one or moreindependent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₂R³¹,—SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

each of R³¹, R³², and R³³ is independently H or C₁₋₁₀alkyl, wherein theC₁₋₁₀alkyl is unsubstituted or is substituted with one or more aryl,heteroalkyl, heterocyclyl, or hetaryl group, wherein each of said alkyl,aryl, heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or issubstituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃, —O-aryl,—OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl),—NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl), —C(O)(C₁₋₁₀alkyl-aryl),—C(O)(aryl), —CO₂—C₁₋₁₀alkyl, —CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl,—C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵,—C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl), —O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂,—CN, —S(O)₀₋₂C₁₋₁₀alkyl, —S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂aryl,—SO₂N(aryl), —SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or—SO₂NR³⁴R³⁵ s;

-   R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are taken    together with the nitrogen atom to which they are attached to form a    3-10 membered saturated or unsaturated ring; wherein said ring is    independently unsubstituted or is substituted by one or more    —NR³¹R³², hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or    O-aryl, and wherein said 3-10 membered saturated or unsaturated ring    independently contains 0, 1, or 2 more heteroatoms in addition to    the nitrogen atom;

each of R⁷ and R⁸ is independently hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,aryl, heteroaryl, heterocyclyl or C₃₋₁₀cycloalkyl, each of which exceptfor hydrogen is unsubstituted or is substituted by one or moreindependent R⁶; and

R⁶ is halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, eachof which is unsubstituted or is substituted with one or more independenthalo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², or—NR³⁴R³⁵.

In some embodiments the compound Formula I-B, is the compound wherein M₁is:

In yet another aspect, the invention provides a compound of Formula IV-Aor Formula IV-B:

or a pharmaceutically acceptable salt thereof, wherein:

X₁ is N or C-E¹, X₂ is N, and X₃ is C; or X₁ is N or C-E¹, X₂ is C, X₃is N, and X₄ is CR⁹ or N;

R₁ is H, -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl,-L-aryl, -L-heteroaryl, -L-C₁₋₁₀alkylaryl, -L-C₁₋₁₀alkylhetaryl,-L-C₁₋₁₀alkylheterocylyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl,-L-C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, -L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,-L-heteroalkyl, -L-heteroalkylaryl, -L-heteroalkylheteroaryl,-L-heteroalkyl-heterocylyl, -L-heteroalkyl-C₃₋₈cycloalkyl, -L-aralkyl,-L-heteroaralkyl, or -L-heterocyclyl, each of which is unsubstituted oris substituted by one or more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

k is 0 or 1;

E¹ and E² are independently -(W¹)_(j)-R⁴;

j in E¹ or j in E², is independently 0 or 11;

W¹ is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)S(O)—, —N(R⁷)S(O)₂, —C(O)O—, —CH(R⁷)N(C(O)OR⁸)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—;

W² is —O—, —NR⁷—, —S(O)₀₋₂, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)C(O)N(R⁸)—, —N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—,—CH(R⁷)N(C(O)OR⁸)—, —CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—,—CH(R⁷)C(O)N(R⁸)—, —CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or—CH(R⁷)N(R⁸)S(O)₂—;

R³ and R⁴ are independently hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³², aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkylC₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₁₋₁₀alkyl-C₂₋₁₀alkenyl, C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl,C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl,heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, hetaryl C₃₋₈cycloalkyl,heteroalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein eachof said aryl or heteroaryl moiety is unsubstituted or is substitutedwith one or more independent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵,—NO₂, —CN, —S(O)₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

R² is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,bicyclic aryl, substituted monocyclic aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₁₋₁₀alkyl-C₂₋₁₀alkenyl, C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₂₋₁₀alkyl-monocyclicaryl, monocyclic aryl-C₂₋₁₀alkyl, C₁₋₁₀alkylbicycloaryl,bicycloaryl-C₁₋₁₀alkyl, substituted C₁₋₁₀alkylaryl, substitutedaryl-C₁₋₁₀alkyl, C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₂₋₁₀alkenyl-C₁₋₁₀alkyl,C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl, C₂₋₁₀alkenylhetaryl,C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl,C₂₋₁₀alkynylheteroalkyl, C₂₋₁₀alkynylheterocylyl,C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxy C₁₋₁₀alkyl,C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl, heterocyclyl,heteroalkyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,aryl-heterocyclyl, or hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl,hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl, hetaryl-heteroalkyl, orhetaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroarylmoiety is unsubstituted, or wherein each of bicyclic aryl, heteroarylmoiety or monocyclic aryl moiety is substituted with one or moreindependent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₂R³¹,—SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₂R³², —C(═S)OR³¹, C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

R⁵ is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³²;

each of R³¹, R³², and R³³ is independently H or C₁₋₁₀alkyl, wherein theC₁₋₁₀alkyl is unsubstituted or is substituted with one or more aryl,heteroalkyl, heterocyclyl, or hetaryl group, wherein each of said aryl,heteroalkyl, heterocyclyl, or hetaryl group is unsubstituted or issubstituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃, —O-aryl,—OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl),—NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl), —C(O)(C₁₋₁₀alkyl-aryl),—C(O)(aryl), —CO₂—C₁₋₁₀alkyl, —CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl,—C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵,—C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl), —O-aryl, —N(aryl)(C₁₋₁₀alkyl), NO₂,—CN, S(O)₀₋₂C₁₋₁₀alkyl, S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂ aryl,—SO₂N(aryl), —SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or—SO₂NR³⁴R³⁵;

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen atom;

each of R⁷ and R⁸ is independently hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,aryl, heteroaryl, heterocyclyl or C₃₋₁₀cycloalkyl, each of which exceptfor hydrogen is unsubstituted or is substituted by one or moreindependent R⁶;

R⁶ is halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl; aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, whereineach of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl,or hetaryl group is unsubstituted or is substituted with one or moreindependent halo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², orNR³⁴R³⁵; and

R⁹ is H, halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl; aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, whereineach of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl,or hetaryl group is unsubstituted or is substituted with one or moreindependent halo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², orNR³⁴R³⁵.

In some embodiments of the compound of Formula IV-A or Formula IV-B, X₄is CR⁹. In other embodiments, X₄ is N.

The compounds of the invention inhibit a protein kinase. In someembodiments of the compounds of the invention, the compound inhibits alipid kinase. In other embodiments of the compounds of the invention,the compound inhibits a protein kinase and a lipid kinase. In someembodiments of the compounds of the invention, the compound inhibits akinase selected from the group consisting of PI3 kinase α, PI3 kinase β,PI3 kinase γ, PI3 kinase δ, DNA-PK, mTor C (including mTorC1 andmTorC2), Abl. VEGFR, EphB4, Tie2, Flt3, PDGFR, RET, InsR, ATM, ATR,hSmg-1, and IGFR.

In some embodiments, a compound of the invention or a pharmaceuticallyacceptable salt thereof inhibits mTor at an IC50 value of less thanabout 100 nM. In other embodiments, a compound of the invention or apharmaceutically acceptable salt thereof inhibits mTor at an IC50 valueof less than about 10 nM.

In a further aspect, the invention provides a composition comprising acompound of Formula I′-A′, I (including I-A and I-B), II-A (includingII-A-1, II-A-1a, and II-A-2), II-B (including II-B-1 and II-B-2), III(including III-A and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B(including IV-B-1 and IV-B-2), C, 3-6, or N-3, or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.

In some embodiments of the compositions of the invention, a compound ofFormula I′-A′, I (including I-A and I-B), II-A (including II-A-1,II-A-1a, and II-A-2), II-B (including II-B-1 and II-B-2), III (includingIII-A and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (includingIV-B-1 and IV-B-2), C, 3-6, or N-3, or a pharmaceutically acceptablesalt thereof, is a compound wherein E² is —H; X₁ and X₂ are N; R₁ is-L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkylheterocylyl, orL-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³; R³ is hydrogen, —OH, —OR³¹, NR³¹R³², —C(O)R³¹,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, aryl, hetaryl, C₁₋₄alkyl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, or heterocyclyl, wherein each of said aryl or heteroarylmoiety is unsubstituted or is substituted with one or more independentalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³¹R³², —C(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³² s, and wherein each ofsaid alkyl, cycloalkyl, or heterocyclyl moiety is unsubstituted or issubstituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl,—NR³¹R³²NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²; andwherein -(W²)_(k)- is —NR⁷—, —N(R⁷)C(O)— or —N(R⁷)S(O)₂—.

In some embodiments of the compositions of the invention, a compound ofFormula I′-A′, I (including I-A and I-B), II-A (including II-A-1,II-A-1a, and II-A-2), II-B (including II-B-1 and II-B-2), III (includingIII-A and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (includingIV-B-1 and IV-B-2), C, 3-6, or N-3, or a pharmaceutically acceptablesalt thereof, is a compound wherein X₄ is CR⁹. In another embodiment, X₄is N.

In some embodiments of the compositions of the invention, a compound ofFormula I′-A′, I (including I-A and I-B), II-A (including II-A-1,II-A-1a, and II-A-2), II-B (including II-B-1 and II-B-2), III (includingIII-A and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (includingIV-B-1 and IV-B-2), C, 3-6, or N-3, or a pharmaceutically acceptablesalt thereof, is a compound wherein E² is —H. In some embodiments of thecompounds of the invention, X₁ is N and X₂ is N. In other embodiments ofthe compounds of the invention, X₁ is C-E¹ and X₂ is N. In oneembodiment of the compounds of the invention, X₁ is NH and X₂ is C.

In some embodiments of the compositions of the invention, a compound ofFormula I′-A′, I (including I-A and I-B), II-A (including II-A-1,II-A-1a, and II-A-2), II-B (including II-B-1 and II-B-2), III (includingIII-A and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (includingIV-B-1 and IV-B-2), C, 3-6, or N-3, or a pharmaceutically acceptablesalt thereof, is a compound wherein R₃₁ and R₃₂ are —H.

In some embodiments of the compositions of the invention, a compound ofFormula I′-A′, I (including I-A and I-B), II-A (including II-A-1,II-A-1a, and II-A-2), II-B (including II-B-1 and II-B-2), III (includingIII-A and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (includingIV-B-1 and IV-B-2), C, 3-6, or N-3, or a pharmaceutically acceptablesalt thereof, is a compound wherein -(W²)_(k)- is —NR⁷—, —N(R⁷)C(O)—,—N(R⁷)C(O)N(R⁸)—, or —N(R⁷)S(O)₂—. In other embodiments, -(W²)_(k)- is—NH—. In another embodiment, -(W²)_(k)- is —(CH)₂—. In yet anotherembodiment, -(W²)_(k)- is —NHC(O)—. In a further embodiment of thecompounds of the invention, -(W²)_(k)- is —N(R⁷)C(O)N(R⁸)—. In anotherembodiment of the compounds of the invention, -(W²)_(k)- is —NHS(O)₂—.

In some embodiments of the compositions of the invention, a compound ofFormula I′-A′, I (including I-A and I-B), II-A (including II-A-1,II-A-1a, and II-A-2), II-B (including II-B-1 and II-B-2), III (includingIII-A and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (includingIV-B-1 and IV-B-2), C, 3-6, or N-3, or a pharmaceutically acceptablesalt thereof, is a compound wherein R₁ is -L-C₁₋₁₀alkyl,-L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkylheterocylyl, or -L-heterocyclyl, each ofwhich is unsubstituted or is substituted by one or more independent R³,wherein R³ is hydrogen, —OH, —OR³¹, —C(O)R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, orheterocyclyl, wherein each of said aryl, heteroaryl, alkyl, cycloalkyl,or heterocyclyl moiety is unsubstituted or is substituted with one ormore alkyl or —OH. In some embodiments of the compounds of theinvention, R₁ is unsubstituted or is substituted with C₁₋₁₀alkyl orcycloC₁₋₁₀alkyl.

In some embodiments of the compositions of the invention, a compound ofFormula I′-A′, I (including I-A and I-B), II-A (including II-A-1,II-A-1a, and II-A-2), II-B (including II-B-1 and II-B-2), III (includingIII-A and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (includingIV-B-1 and IV-B-2), C, 3-6, or N-3, or a pharmaceutically acceptablesalt thereof, is a compound wherein R² is alkyl. In yet otherembodiments, R² is methyl. In other embodiments of the compounds of theinvention, R² is isopropyl. In some embodiments, R² is cycloalkyl. Inother embodiments, R² is cyclopropyl.

In another aspect of the invention, a method is provided of inhibitingactivity of a protein kinase and/or a lipid kinase present in a cell,comprising contacting said cell with an effective amount of a compoundof Formula I′-A′, I (including I-A and I-B), II-A (including II-A-1,II-A-1a, and II-A-2), II-B (including II-B-1 and II-B-2), III (includingIII-A and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (includingIV-B-1 and IV-B-2), C, 3-6, or N-3.

In some embodiments of the methods of the invention, a compound ofFormula I′-A′, I (including I-A and I-B), II-A (including II-A-1,II-A-1a, and II-A-2), II-B (including II-B-1 and II-B-2), III (includingIII-A and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (includingIV-B-1 and IV-B-2), C, 3-6, or N-3, or a pharmaceutically acceptablesalt thereof, is a compound wherein E² is —H; X₁ and X₂ are N; R₁ is-L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkylheterocylyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³; R³ is hydrogen, —OH, OR³¹, —NR³¹R³², —C(O)R³¹,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, aryl, hetaryl, C₁₋₄alkyl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, or heterocyclyl, wherein each of said aryl or heteroarylmoiety is unsubstituted or is substituted with one or more independentalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —C(═O)SR³¹, —SC(═O)OR³¹,—P(O)OR³¹OR³², or —SC(═O)NR³¹R³² s, and wherein each of said alkyl,cycloalkyl, or heterocyclyl moiety is unsubstituted or is substitutedwith one or more alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo,—OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹,—CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²; and wherein -(W²)_(k)- is—NR⁷—, —N(R⁷)C(O)— or —N(R⁷)S(O)₂—.

In some embodiments of the methods of the invention, a compound ofFormula I′-A′, I (including I-A and I-B), II-A (including II-A-1,II-A-1a, and II-A-2), II-B (including II-B-1 and II-B-2), III (includingIII-A and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (includingIV-B-1 and IV-B-2), C, 3-6, or N-3, or a pharmaceutically acceptablesalt thereof, is a compound wherein X₄ is CR⁹. In another embodiment, X₄is N.

In some embodiments of the methods of the invention, a compound ofFormula I′-A′, I (including I-A and I-B), II-A (including II-A-1,II-A-1a, and II-A-2), II-B (including II-B-1 and II-B-2), III (includingIII-A and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (includingIV-B-1 and IV-B-2), C, 3-6, or N-3, or a pharmaceutically acceptablesalt thereof, is a compound wherein E² is —H. In some embodiments of thecompounds of the invention, X₁ is N and X₂ is N. In other embodiments ofthe compounds of the invention, X₁ is C-E¹ and X₂ is N. In oneembodiment of the compounds of the invention, X₁ is NH and X₂ is C.

In some embodiments of the methods of the invention, a compound ofFormula I′-A′, I (including I-A and I-B), II-A (including II-A-1,II-A-1a, and II-A-2), II-B (including II-B-1 and II-B-2), III (includingIII-A and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (includingIV-B-1 and IV-B-2), C, 3-6, or N-3, or a pharmaceutically acceptablesalt thereof, is a compound wherein R₃₁ and R₃₂ are —H.

In some embodiments of the methods of the invention, a compound ofFormula I′-A′, I (including I-A and I-B), II-A (including II-A-1,II-A-1a, and II-A-2), II-B (including II-B-1 and II-B-2), III (includingIII-A and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (includingIV-B-1 and IV-B-2), C, 3-6, or N-3, or a pharmaceutically acceptablesalt thereof, is a compound wherein -(W²)_(k)- is —NR⁷—, —N(R⁷)C(O)—,—N(R⁷)C(O)N(R⁸)—, or —N(R⁷)S(O)₂—. In other embodiments, -(W²)_(k)- is—NH—. In another embodiment, -(W²)_(k)- is —(CH)₂—. In yet anotherembodiment, -(W²)_(k)- is —NHC(O)—. In a further embodiment of thecompounds of the invention, -(W²)_(k)- is —N(R⁷)C(O)N(R⁸)—. In anotherembodiment of the compounds of the invention, -(W²)_(k)- is —NHS(O)₂—.

In some embodiments of the methods of the invention, a compound ofFormula I′-A′, I (including I-A and I-B), II-A (including II-A-1,II-A-1a, and II-A-2), II-B (including II-B-1 and II-B-2), III (includingIII-A and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (includingIV-B-1 and IV-B-2), C, 3-6, or N-3, or a pharmaceutically acceptablesalt thereof, is a compound wherein R₁ is -L-C₁₋₁₀alkyl,-L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkylheterocylyl, or -L-heterocyclyl, each ofwhich is unsubstituted or is substituted by one or more independent R³,wherein R³ is hydrogen, —OH, —OR³¹, —C(O)R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, orheterocyclyl, wherein each of said aryl, heteroaryl, alkyl, cycloalkyl,or heterocyclyl moiety is unsubstituted or is substituted with one ormore alkyl or —OH. In some embodiments of the compounds of theinvention, R₁ is unsubstituted or is substituted with C₁₋₁₀alkyl orcycloC₁₋₁₀alkyl.

In some embodiments of the compositions of the invention, a compound ofFormula I′-A′, I (including I-A and I-B), II-A (including II-A-1,II-A-1a, and II-A-2), II-B (including II-B-1 and II-B-2), III (includingIII-A and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (includingIV-B-1 and IV-B-2), C, 3-6, or N-3, or a pharmaceutically acceptablesalt thereof, is a compound wherein R² is alkyl. In yet otherembodiments, R² is methyl. In other embodiments of the compounds of theinvention, R² is isopropyl. In some embodiments, R² is cycloalkyl. Inother embodiments, R² is cyclopropyl.

In some of the embodiments of the methods of the invention, theinhibiting takes place in a subject suffering from a disorder selectedfrom the group consisting of cancer, bone disorder, inflammatorydisease, immune disease, nervous system disease, metabolic disease,respiratory disease, and cardiac disease. Further, in some embodimentsof the method of the invention a second therapeutic agent isadministered.

In some embodiments, one or more compounds of the invention yieldselective inhibition of mTor-mediated signal transduction as compared toPI3K. In some other embodiments, the compounds provided herein caninhibit mTor-mediated activity more effectively than rapamycin, henceproviding an alternative treatment for rapamycin-resistant conditions.

In some embodiments, one or more compounds of the invention selectivelyinhibits both mTorC1 and mTorC2 activity relative to all type Iphosphatidylinositol 3-kinases (PI3-kinase) consisting of PI3-kinase α,PI3-kinase β, PI3-kinase γ, and PI3-kinase δ. In some embodiments, oneor more compounds of the invention selectively inhibits both mToractivity with an IC50 value of about 100 nM, 50 nM, 10 nM, 5 nM, 100 pM,10 pM or even 1 pM, or less as ascertained in an in vitro kinase assay.In some embodiments, one or more compounds of the invention issubstantially ineffective in inhibiting a type I PI3-kinase at aconcentration of 100 nM, 200 nM, 500 nM, or 1 uM, 5 uM or 10 uM, orhigher in an in vitro kinase assay.

In some embodiments, one or more compounds of the invention inhibitsphosphorylation of Akt (S473) and Akt (T308) more effectively thanrapamycin when tested at a comparable molar concentration in an in vitrokinase assay.

In some embodiments, one or more compounds of the invention competeswith ATP for binding to ATP-binding site on mTorC1 and/or mTorC2.

In some embodiments, one or more compounds of the invention causesapoptosis of said cell or cell cycle arrest.

The present invention provides methods and composition for inhibitingcell proliferation. In one embodiment, the method comprises contacting acell with one or more compounds of the invention that selectivelyinhibits mTorC1 and/or mTorC2 activity relative to one or more type Iphosphatidylinositol 3-kinases (PI3-kinase) ascertained by an in vitrokinase assay, wherein the one or more type I PI3-kinase is selected fromthe group consisting of PI3-kinase α, PI3-kinase β, PI3-kinase γ, andPI3-kinase δ. In some embodiment, the inhibition of cell-proliferationis evidenced by an assay selected from the group consisting of an MTScell proliferation assay, a resazurin assay, a colony formation assay,flow cytometry, and a cell division tracker dye assay.

In a separate and related embodiment, the present invention provides amethod of inhibiting phosphorylation of both Akt (S473) and Akt (T308)in a cell, comprising contacting a cell with an effective amount of oneor more compounds of the invention that selectively inhibits both mTorC1and mTorC2 activity relative to one or more type I phosphatidylinositol3-kinases (PI3-kinase) as ascertained by a cell-based assay or an invitro kinase assay, wherein the one or more type I PI3-kinase isselected from the group consisting of PI3-kinase α, PI3-kinase β,PI3-kinase γ, and PI3-kinase δ, thereby Akt phosphorylation at residuesS473 and T308 is simultaneously inhibited.

In another embodiment, the present invention provides a method ofsubstantially inhibiting proliferation of a neoplastic cell comprisingcontacting the cell with an effective amount of one or more compounds ofthe invention that inhibits full activation of Akt in a cell and ananti-cancer agent, wherein said inhibition of cell proliferation isenhanced through a synergistic effect of said compound and saidanti-cancer agent.

In yet another embodiment, the present invention provides a method ofameliorating a medical condition mediated by mTorC1 and/or mTorC2,comprising administering to a subject in need thereof a therapeuticallyeffective amount of one or more compounds of the invention thatselectively inhibits mTorC1 and/or mTorC2 activity relative to one ormore type I phosphatidylinositol 3-kinases (PI3-kinase) as ascertainedin a cell-based assay or an in vitro kinase assay, wherein the one ormore type I PI3-kinase is selected from the group consisting ofPI3-kinase α, PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

Also provided in the present invention is a combination treatment for asubject diagnosed with or at risk of a neoplastic condition, comprisingadministering to said subject a therapeutically effective amount of oneor more compounds of the invention that substantially inhibits fullactivation of Akt in a cell and an anti-cancer agent, wherein theefficacy of said treatment is enhanced through a synergistic effect ofsaid compound and said anti-cancer agent.

In some embodiment, the compound utilized in the subject methods is acompound that selectively inhibits both mTorC1 and mTORC2 activityrelative to all type I phosphatidylinositol 3-kinases (PI3-kinase)consisting of PI3-kinase α, PI3-kinase β, PI3-kinase γ, and PI3-kinaseδ.

In some other embodiments, the anti-cancer agent utilized in the subjectmethods can include but are not limited to rapamycin, Gleevec, orderivative thereof, which inhibits a mammalian target of rapamycin orGleevec.

A wide variety of neoplastic conditions can be treated using one or moreof the subject compositions. Such conditions include but are not limitedto neoplastic condition such as restenosis, cancer selected from B celllymphoma, T cell lymphoma, non small cell lung carcinoma, and leukemia,or an autoimmune disorder.

The compound of the invention and/or the anti-cancer agent can beadministered parenterally, orally, intraperitoneally, intravenously,intraarterially, transdermally, intramuscularly, liposomally, via localdelivery by catheter or stent, subcutaneously, intraadiposally, orintrathecally.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference in their entirety as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1A-1B summarizes the results of cell proliferation inhibitionassays performed with a wide range of neoplastic cell lines in vitrousing conventional anti-cancer drugs or a compound of the presentinvention such as a compound of Table 1. The experimental procedure isdescribed herein, e.g., in Example 17. The degree of inhibition isreported in the Figure herein as +, ++, +++, ++++, or +++++ in the orderof increased magnitude in inhibiting cell proliferation. The resultsdemonstrate that one or more compounds of the invention yields 50%inhibition of cell proliferation at a concentration that is one or twoorders of magnitude less than that of the conventional anti-cancer drugswhen tested under the same condition.

FIG. 2 is a western blot illustrating the dose dependent effect of acompound of Table 1 in inhibiting pAKT phosphorylation at residue 47 aswell as other signalling molecules downstream of mTOR including p4EBP1and pRAS40. The results demonstrate that the subject mTOR inhibitor ofthe invention is more effective in inhibiting Akt phosphorylation ascompared to rapamycin.

FIG. 3A depicts the in vivo effect of a compound of Table 1 of thesubject invention in inhibiting tumor growth in a tumor model such asthe U87 human glioblastoma xenograft mouse model over a course of about14 study days upon administration of the compound at the dose of 3mg/kg, 1 mg/kg, or 0.3 mg/kg. FIG. 3B shows the test animals and thesize of the tumor taken from the negative control animal (PEG400treated) or from the test animals treated with 0.3 mg/kg, 1 mg/kg, or 3mg/kg of a compound of Table 1. FIG. 3C is a plot of body weight of thenegative control and test animals measured over the course of treatment.The results demonstrate that the compound is well tolerated and nosignificant weight loss is detected during the treatment period, andthat tumor growth is significantly inhibited by administration of one ormore compounds of the present invention under the conditions tested.

FIG. 4A illustrates an experimental procedure for assessing the abilityof the compounds of the invention to inhibit mTOR signalling, especiallyphosphorylation of AKT(473), PRAS40, S6(240), and 4EBP-1. Thephosphorylation pattern of these signalling molecules are shown in FIG.4B.

FIG. 5 depicts the results of lipid and protein kinase selectivityassays with a compound of Table 1.

FIG. 6 depicts the effects of a compound of Table 1 of the presentinvention on PC3 cell proliferation, PC3 pAKT activation, and primarytumor cell line proliferation. Additionally, the specificity of acompound of Table 1 was tested by culturing Jurakt cells in whole bloodto test for non-specific binding/inactivation of the one or morecompounds by components of whole blood.

FIG. 7A-7B depict the effect of a compound of Table 1 of the presentinvention on cellular proliferation and PI3K pathway activation ascompared to rapamycin. FIG. 7A depicts a graph showing the dose responsecurve of PC3 cell proliferation in response to rapamycin and a compoundof the invention from Table 1. FIG. 7B depicts a western blot analysisof inhibition of phosphorylation of PI3K pathway targets by one or morecompounds selected from Table 1 as compared to rapamycin.

FIG. 8A-8B depicts a comparison of the effect of a compound of Table 1of the present invention on the proliferation of the indicated celllines. FIG. 8A depicts the IC₅₀ of the compound for inhibition of celllines derived from lung and colon and lists the respective proliferationactivating mutations associated with those cell lines. FIG. 8B depictsthe effects of a compound of Table 1 of the present invention onproliferation of cell lines comprising the various activating mutationsindicated in comparison to the inhibition provided by a Pan PI3 kinaseinhibitor or a Pan PI3 kinase inhibitor that also inhibits mTOR.

FIG. 9A-9B depict the effects of a compound of Table 1 of the presentinvention on cell cycle progression in HCT 116 and SW620 cells ascompared to various other compounds. FIG. 9A depicts the inhibitingeffect of the compound at 500 nM on cell cycle progression as comparedto DMSO vehicle control and as compared to 10 uM doxorubicin. FIG. 9Bdepicts the effect of the indicated compounds on the population of cellsresiding in G₀/G₁ phase during culture for two different cell lines.

FIG. 10 depicts a western blot analysis of the effect of a compound ofTable 1 of the present invention on phosphorylation in tumor cells froma U87-MG xenograft tumor mouse model.

FIGS. 11A-11D depicts the efficacy of oral administration of a compoundof Table 1 of the present invention for inhibiting growth of U87-MG,A549, ZR-75-1, and 786-O xenograft tumors in female athymic nude mice.

FIG. 12 depicts the results of TUNEL staining of the tumor mass ofU87-MG xenograft tumors excised from mice, which were administeredvehicle, 1 mg/kg, or 3 mg/kg of the compound of the invention orally.These results show increased in vivo apoptosis in the presence of acompound of Table 1 of the present invention. FIG. 12 further depictsthe size of the excised U87 tumors which decreases with an increasingdose of a compound of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions may occur to those skilled in theart without departing from the invention. It should be understood thatvarious alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe appended claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs. All patents and publicationsreferred to herein are incorporated by reference.

As used in the specification and claims, the singular form “a”, “an” and“the” include plural references unless the context clearly dictatesotherwise.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound described herein that is sufficient toeffect the intended application including but not limited to diseasetreatment, as defined below. The therapeutically effective amount mayvary depending upon the intended application (in vitro or in vivo), orthe subject and disease condition being treated, e.g., the weight andage of the subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that willinduce a particular response in target cells, e.g. reduction of plateletadhesion and/or cell migration. The specific dose will vary depending onthe particular compounds chosen, the dosing regimen to be followed,whether it is administered in combination with other compounds, timingof administration, the tissue to which it is administered, and thephysical delivery system in which it is carried.

As used herein, “treatment” or “treating,” or “palliating” or“ameliorating” is used interchangeably herein. These terms refer to anapproach for obtaining beneficial or desired results including but notlimited to a therapeutic benefit and/or a prophylactic benefit. Bytherapeutic benefit is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the subject, notwithstanding that thesubject may still be afflicted with the underlying disorder. Forprophylactic benefit, the compositions may be administered to a subjectat risk of developing a particular disease, or to a subject reportingone or more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made.

A “therapeutic effect,” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit as described above. Aprophylactic effect includes delaying or eliminating the appearance of adisease or condition, delaying or eliminating the onset of symptoms of adisease or condition, slowing, halting, or reversing the progression ofa disease or condition, or any combination thereof.

The term “co-administration,” “administered in combination with,” andtheir grammatical equivalents, as used herein, encompass administrationof two or more agents to an animal so that both agents and/or theirmetabolites are present in the subject at the same time.Co-administration includes simultaneous administration in separatecompositions, administration at different times in separatecompositions, or administration in a composition in which both agentsare present.

The term “pharmaceutically acceptable salt” refers to salts derived froma variety of organic and inorganic counter ions well known in the artand include, by way of example only, sodium, potassium, calcium,magnesium, ammonium, tetraalkylammonium, and the like, when the moleculecontains an acidic functionality; and when the molecule contains a basicfunctionality, salts of organic or inorganic acids, such ashydrochloride, hydrobromide, tartrate, mesylate (methane sulfonate),ethane sulfonate, acetate, maleate, oxalate, phosphate, and the like. Ina compound with more than one basic moiety, more than one of the basicmoieties may be converted to the salt form, including but not limited toa bis- or tris-salt. Alternatively, a compound having more than onebasic moiety may form a salt at only one of the basic moieties.

The terms “antagonist” and “inhibitor” are used interchangeably, andthey refer to a compound having the ability to inhibit a biologicalfunction of a target protein, whether by inhibiting the activity orexpression of the target protein. Accordingly, the terms “antagonist”and “inhibitors” are defined in the context of the biological role ofthe target protein. While preferred antagonists herein specificallyinteract with (e.g. bind to) the target, compounds that inhibit abiological activity of the target protein by interacting with othermembers of the signal transduction pathway of which the target proteinis a member are also specifically included within this definition. Apreferred biological activity inhibited by an antagonist is associatedwith the development, growth, or spread of a tumor.

The term “agonist” as used herein refers to a compound having theability to initiate or enhance a biological function of a targetprotein, whether by inhibiting the activity or expression of the targetprotein. Accordingly, the term “agonist” is defined in the context ofthe biological role of the target polypeptide. While preferred agonistsherein specifically interact with (e.g. bind to) the target, compoundsthat initiate or enhance a biological activity of the target polypeptideby interacting with other members of the signal transduction pathway ofwhich the target polypeptide is a member are also specifically includedwithin this definition.

As used herein, “agent” or “biologically active agent” refers to abiological, pharmaceutical, or chemical compound or other moiety.Non-limiting examples include a simple or complex organic or inorganicmolecule, a peptide, a protein, an oligonucleotide, an antibody, anantibody derivative, antibody fragment, a vitamin derivative, acarbohydrate, a toxin, or a chemotherapeutic compound. Various compoundscan be synthesized, for example, small molecules and oligomers (e.g.,oligopeptides and oligonucleotides), and synthetic organic compoundsbased on various core structures. In addition, various natural sourcescan provide compounds for screening, such as plant or animal extracts,and the like.

“Signal transduction” is a process during which stimulatory orinhibitory signals are transmitted into and within a cell to elicit anintracellular response. A modulator of a signal transduction pathwayrefers to a compound which modulates the activity of one or morecellular proteins mapped to the same specific signal transductionpathway. A modulator may augment (agonist) or suppress (antagonist) theactivity of a signaling molecule.

An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent”refers to any agent useful in the treatment of a neoplastic condition.One class of anti-cancer agents comprises chemotherapeutic agents.“Chemotherapy” means the administration of one or more chemotherapeuticdrugs and/or other agents to a cancer patient by various methods,including intravenous, oral, intramuscular, intraperitoneal,intravesical, subcutaneous, transdermal, buccal, or inhalation or in theform of a suppository.

The term “cell proliferation” refers to a phenomenon by which the cellnumber has changed as a result of division. This term also encompassescell growth by which the cell morphology has changed (e.g., increased insize) consistent with a proliferative signal.

The term “selective inhibition” or “selectively inhibit” refers to abiologically active agent refers to the agent's ability topreferentially reduce the target signaling activity as compared tooff-target signaling activity, via direct or indirect interaction withthe target.

“mTorC1 and/or mTorC2 activity” as applied to a biologically activeagent refers to the agent's ability to modulate signal transductionmediated by mTorC1 and/or mTorC2. For example, modulation of mTorC1and/or mTorC2 activity is evidenced by alteration in signaling outputfrom the PI3K/Akt/mTor pathway.

The term “B-ALL” as used herein refers to B-cell Acute LymphoblasticLeukemia.

“Subject” refers to an animal, such as a mammal, for example a human.The methods described herein can be useful in both human therapeuticsand veterinary applications. In some embodiments, the subject is amammal, and in some embodiments, the subject is human.

“Radiation therapy” means exposing a subject, using routine methods andcompositions known to the practitioner, to radiation emitters such asalpha-particle emitting radionuclides (e.g., actinium and thoriumradionuclides), low linear energy transfer (LET) radiation emitters(i.e. beta emitters), conversion electron emitters (e.g. strontium-89and samarium-153-EDTMP, or high-energy radiation, including withoutlimitation x-rays, gamma rays, and neutrons.

An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent”refers to any agent useful in the treatment of a neoplastic condition.One class of anti-cancer agents comprises chemotherapeutic agents.“Chemotherapy” means the administration of one or more chemotherapeuticdrugs and/or other agents to a cancer patient by various methods,including intravenous, oral, intramuscular, intraperitoneal,intravesical, subcutaneous, transdermal, buccal, or inhalation or in theform of a suppository.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein. Thus, the term “prodrug” refers to aprecursor of a biologically active compound that is pharmaceuticallyacceptable. A prodrug may be inactive when administered to a subject,but is converted in vivo to an active compound, for example, byhydrolysis. The prodrug compound often offers advantages of solubility,tissue compatibility or delayed release in a mammalian organism (see,e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier,Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al.,“Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14,and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche,American Pharmaceutical Association and Pergamon Press, 1987, both ofwhich are incorporated in full by reference herein. The term “prodrug”is also meant to include any covalently bonded carriers, which releasethe active compound in vivo when such prodrug is administered to amammalian subject. Prodrugs of an active compound, as described herein,may be prepared by modifying functional groups present in the activecompound in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent active compound. Prodrugsinclude compounds wherein a hydroxy, amino or mercapto group is bondedto any group that, when the prodrug of the active compound isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of a hydroxy functional group, or acetamide, formamide andbenzamide derivatives of an amine functional group in the activecompound and the like.

The term “in vivo” refers to an event that takes place in a subject'sbody.

The term “in vitro” refers to an event that takes places outside of asubject's body. For example, an in vitro assay encompasses any assay runoutside of a subject assay. In vitro assays encompass cell-based assaysin which cells alive or dead are employed. In vitro assays alsoencompass a cell-free assay in which no intact cells are employed.

Unless otherwise stated, the connections of compound name moieties areat the rightmost recited moiety. That is, the substituent name startswith a terminal moiety, continues with any linking moieties, and endswith the linking moiety. For example, hetarylthio C₁₋₄alkyl has aheteroaryl group connected through a thio sulfur to a C₁₋₄alkyl radicalthat connects to the chemical species bearing the substituent. Thiscondition does not apply where a formula such as, for example“-L-C₁₋₁₀alkyl-C₃₋₈ cycloalkyl” is represented. In such case, theterminal group is a C₃₋₈ cycloalkyl group attached to a linking C₁₋₁₀alkyl moiety which is attached to an element L, which is itselfconnected to the chemical species bearing the substituent.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of atoms that constitutesuch compounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds ofthe present invention, whether radioactive or not, are encompassedwithin the scope of the present invention.

As used herein, for example, “C₁₋₄alkyl” is used to mean an alkyl having1-4 carbons—that is, 1, 2, 3, or 4 carbons in a straight or branchedconfiguration. In all embodiments of this invention, the term “alkyl”includes both branched and straight chain alkyl groups, or cyclichydrocarbon groups, or a combination thereof. Alkyl groups are fullysaturated, unsubstituted or substituted, and can include di- andmultivalent radicals, having the number of carbon atoms designated (i.e.C₁-C₁₀ means one to ten carbons and C₂-C₁₀ means two to ten carbons).Typical alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl,isooctyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl,octadecyl, eicosyl, and the like.

The term “halo” or “halogen” refers to fluoro, chloro, bromo, or iodo.

The term “haloalkyl” refers to an alkyl group substituted with one ormore halo groups, for example chloromethyl, 2-bromoethyl, 3-iodopropyl,trifluoromethyl, perfluoropropyl, 8-chlorononyl, and the like.

The term “acyl” refers to the structure —C(═O)—R, in which R is ageneral substituent variable such as, for example R¹ described above.Examples include, but are not limited to, alkylketo,(bi)(cyclo)alkylketo, (cyclo)alkenylketo, alkynylketo, arylketo,hetarylketo, heterocyclylketo, heterobicycloalkylketo, spiroalkylketo.An acyl moiety is unsubstituted or is substituted on R.

Unless otherwise specified, the term “cycloalkyl” refers to a 3-8 carboncyclic aliphatic ring structure that is unsubstituted or substitutedwith, for example, alkyl, hydroxy, oxo, or halo, such as cyclopropyl,methylcyclopropyl, cyclobutyl, cyclopentyl, 2-hydroxycyclopentyl,cyclohexyl, 4-chlorocyclohexyl, cycloheptyl, cyclooctyl, and the like.

The term “C₁₋₁₀alkyl-C₃₋₈cycloalkyl” is used to describe an alkyl group,branched or straight chain and containing 1 to 10 carbon atoms, attachedto a linking cycloalkyl group which contains 3 to 8 carbons, such as forexample, 2-methyl cyclopropyl, and the like. Either portion of themoiety is unsubstituted or substituted.

The term “bicycloalkyl” refers to a structure consisting of twocycloalkyl moieties, unsubstituted or substituted, that have two or moreatoms in common. If the cycloalkyl moieties have exactly two atoms incommon they are said to be “fused”. Examples include, but are notlimited to, bicyclo[3.1.0]hexyl, perhydronaphthyl, and the like. If thecycloalkyl moieties have more than two atoms in common they are said tobe “bridged”. Examples include, but are not limited to,bicyclo[3.2.1]heptyl (“norbornyl”), bicyclo[2.2.2]octyl, and the like.

As used herein, the term “heteroatom” or “ring heteroatom” is meant toinclude oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), andsilicon (Si).

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combinations thereof, consisting of at least onecarbon atoms and at least one heteroatom selected from the groupconsisting of O, N, P, Si and S, and wherein the nitrogen, phosphorus,and sulfur atoms may optionally be oxidized and the nitrogen heteroatommay optionally be quaternized. The heteroatom(s) O, N, P and S and Simay be placed at any interior position of the heteroalkyl group or atthe position at which alkyl group is attached to the remainder of themolecule. The alkyl portion of the moiety is unsubstituted orsubstituted. Examples include, but are not limited to, —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃,—CH═CH—N(CH₃)—CH₃, O—CH₃, —O—CH₂—CH₃, and —CN. Up to two or threeheteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃. Similarly, the term “heteroalkylene” by itself or aspart of another substituent means a divalent radical derived fromheteroalkyl, as exemplified, but not limited by, —CH₂—CH₂—S—CH₂—CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylene groups, heteroatoms can alsooccupy either or both of the chain termini (e.g., alkyleneoxo,alkylenedioxo, alkyleneamino, alkylenediamino, and the like). Stillfurther, for alkylene and heteroalkylene linking groups, no orientationof the linking group is implied by the direction in which the formula ofthe linking group is written. For example, the formula —C(O)OR′—represents both —C(O)OR′— and —R′OC(O)—. As described above, heteroalkylgroups, as used herein, include those groups that are attached to theremainder of the molecule through a heteroatom, such as —C(O)R′,—C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where “heteroalkyl” isrecited, followed by recitations of specific heteroalkyl groups, such as—NR′R″ or the like, it will be understood that the terms heteroalkyl and—NR′R″ are not redundant or mutually exclusive. Rather, the specificheteroalkyl groups are recited to add clarity. Thus, the term“heteroalkyl” should not be interpreted herein as excluding specificheteroalkyl groups, such as —NR′R″ or the like.

The term “heteroalkylaryl” refers to a heteroalkyl group as definedabove which is attached to an aryl group, and may be attached at aterminal point or through a branched portion of the heteroalkyl, forexample, an benzyloxymethyl moiety. Either portion of the moiety isunsubstituted or substituted.

The term “heteroalkylheteroaryl” refers likewise to a heteroalkyl groupwhich is attached to a hetaryl moiety, for example, anethoxymethylpyridyl group. Either portion of the moiety is unsubstitutedor substituted.

The term “heteroalkyl-heterocylyl” refers to a heteroalkyl group asdefined above, which is attached to a heterocyclic group, for example,4(3-aminopropyl)-N-piperazinyl. Either portion of the moiety isunsubstituted or substituted.

The term “heteroalkyl-C₃₋₈cycloalkyl” refers to a heteroalkyl group asdefined above, which is attached to a cyclic alkyl containing 3 to 8carbons, for example, 1-aminobutyl-4-cyclohexyl. Either portion of themoiety is unsubstituted or substituted.

The term “heterobicycloalkyl” refers to a bicycloalkyl structure, whichis unsubstituted or substituted, in which at least one carbon atom isreplaced with a heteroatom independently selected from oxygen, nitrogen,and sulfur.

The term “heterospiroalkyl” refers to a spiroalkyl structure, which isunsubstituted or substituted, in which at least one carbon atom isreplaced with a heteroatom independently selected from oxygen, nitrogen,and sulfur.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, and having from two to ten carbon atoms (ie.C₂-C₁₀ alkenyl). Whenever it appears herein, a numerical range such as“2 to 10” refers to each integer in the given range; e.g., “2 to 10carbon atoms” means that the alkenyl group may consist of 2 carbonatoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. Incertain embodiments, an alkenyl comprises two to eight carbon atoms. Inother embodiments, an alkenyl comprises two to five carbon atoms (e.g.,C₂-C₅ alkenyl). The alkenyl is attached to the rest of the molecule by asingle bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e.,allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Thealkenyl is unsubstituted or substituted. The term “C₂₋₁₀alkenyl-C₃₋₈cycloalkyl” refers to a group containing an alkenyl group,containing 2 to 10 carbons and branched or straight chain, which isattached to a linking cycloalkyl group containing 3 to 8 carbons, suchas, for example 3-prop-3-enyl-cyclopent-1yl, and the like. Eitherportion of the moiety is unsubstituted or substituted.

The term “C₂₋₁₀ alkenyl-heteroalkyl” refers to a group having an alkenylmoiety, containing 2 to 10 carbon atoms and is branched or straightchain, which is attached to a linking heteroalkyl group, such as, forexample, allyloxy, and the like. Either portion of the moiety isunsubstituted or substituted.

The term “C₂₋₁₀ alkynyl-heteroalkyl” refers to a group having an alkynylmoiety, which is unsubstituted or substituted, containing 2 to 10 carbonatoms and is branched or straight chain, which is attached to a linkingheteroalkyl group, such as, for example, 4-but-1-ynoxy, and the like.Either portion of the moiety is unsubstituted or substituted.

The term “haloalkenyl” refers to an alkenyl group substituted with oneor more halo groups.

Unless otherwise specified, the term “cycloalkenyl” refers to a cyclicaliphatic 3 to 8 membered ring structure, optionally substituted withalkyl, hydroxy and halo, having 1 or 2 ethylenic bonds such asmethylcyclopropenyl, trifluoromethylcyclopropenyl, cyclopentenyl,cyclohexenyl, 1,4-cyclohexadienyl, and the like.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one triple bond, having from two to ten carbon atoms (ie. C₂-C₁₀alkynyl). Whenever it appears herein, a numerical range such as “2 to10” refers to each integer in the given range; e.g., “2 to 10 carbonatoms” means that the alkynyl group may consist of 2 carbon atoms, 3carbon atoms, etc., up to and including 10 carbon atoms. In certainembodiments, an alkynyl comprises two to eight carbon atoms. In otherembodiments, an alkynyl has two to five carbon atoms (e.g., C₂-C₅alkynyl). The alkynyl is attached to the rest of the molecule by asingle bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl,and the like. The alkynyl is unsubstituted or substituted.

The term C₂₋₁₀ alkynyl-C₃₋₈cycloalkyl refers to a group containing analkynyl group, containing 2 to 10 carbons and branched or straightchain, which is attached to a linking cycloalkyl group containing 3 to 8carbons, such as, for example 3-prop-3-ynyl-cyclopent-lyl, and the like.Either portion of the moiety is unsubstituted or substituted.

The term, “haloalkynyl” refers to an alkynyl group substituted with oneor more independent halo groups.

“Amino” or “amine” refers to a —NR′R″ moiety, where each R isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloaklylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, unless stated otherwise specifically in thespecification. When both R′ and R″ of a —NR′R″ moiety are not hydrogen,R′ and R″ can be combined with the nitrogen atom to form a 4-, 5-, 6-,or 7-membered ring. For example, —NR′R″ is meant to include, but not belimited to, 1-pyrrolidinyl and 4-morpholinyl. Unless stated otherwisespecifically in the specification, an amino group is optionallysubstituted by one or more substituent which independently is: alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR′, —SR′,—OC(O)—R′, —N(R′)₂, —C(O)R′, —C(O)OR′, —OC(O)N(R′)₂, —C(O)N(R′)₂,—N(R′)C(O)OR′, —N(R′)C(O)R′, —N(R′)C(O)N(R′)₂, N(R′)C(NR′)N(R′)₂,—N(R′)S(O)_(t)R′ (where t is 1 or 2), —S(O)_(t)OR′ (where t is 1 or 2),—S(O)_(t)N(R′)₂ (where t is 1 or 2), or PO₃(R′)₂, where each R′ isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Amide” or “amido” refers to a chemical moiety with formula —C(O)N(R′)₂or —NHC(O)R′, where R′ is selected from the group consisting ofhydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ringcarbon) and heteroalicyclic (bonded through a ring carbon). In someembodiments it is a C₁-C₄ amido or amide radical, which includes theamide carbonyl in the total number of carbons in the radical. The R′₂ of—N(R′)₂ of the amide may optionally be taken together with the nitrogento which it is attached to form a 4-, 5-, 6-, or 7-membered ring. Unlessstated otherwise specifically in the specification, an amido group isoptionally substituted independently by one or more of the substituentsas described herein for alkyl, cycloalkyl, aryl, heteroaryl, orheterocyclyl. An amide may be an amino acid or a peptide moleculeattached to a compound of Formula (I′-A′), thereby forming a prodrug.Any amine, hydroxy, or carboxyl side chain on the compounds describedherein can be amidified. The procedures and specific groups to make suchamides are known to those of skill in the art and can readily be foundin reference sources such as Greene and Wuts, Protective Groups inOrganic Synthesis, 3.sup.rd Ed., John Wiley & Sons, New York, N.Y.,1999, which is incorporated herein by reference in its entirety.

“Aromatic” or “aryl” refers to an aromatic radical with six to ten ringatoms (e.g., C₆-C₁₀ aromatic or C₆-C₁₀ aryl) which has at least one ringhaving a conjugated pi electron system which is carbocyclic (e.g.,phenyl, fluorenyl, and naphthyl). Whenever it appears herein, anumerical range such as “6 to 10” refers to each integer in the givenrange; e.g., “6 to 10 ring atoms” means that the aryl group may consistof 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms.The term includes monocyclic or fused-ring polycyclic (i.e., rings whichshare adjacent pairs of ring atoms) groups. Examples of aryl include,but are not limited to, phenyl, 4-chlorophenyl, 4-fluorophenyl,4-bromophenyl, 3-nitrophenyl, 2-methoxyphenyl, 2-methylphenyl,3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 2-methyl-3-methoxyphenyl,2,4-dibromophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl,2,4,6-trichlorophenyl, 4-methoxyphenyl, naphthyl, 2-chloronaphthyl,2,4-dimethoxyphenyl, 4-(trifluoromethyl)phenyl, and2-iodo-4-methylphenyl. An aryl moiety is unsubstituted or substituted.

“Heteroaryl” or, alternatively, “heteroaromatic”, “hetaryl”, “heteroar”or “hetar” refers to a 5- to 18-membered aromatic radical (e.g., C₅-C₁₃heteroaryl) that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur, and which may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system. Whenever it appears herein, anumerical range such as “5 to 18” refers to each integer in the givenrange; e.g., “5 to 18 ring atoms” means that the heteroaryl group mayconsist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ringatoms. An N-containing “heteroaromatic” or “heteroaryl” moiety refers toan aromatic group in which at least one of the skeletal atoms of thering is a nitrogen atom. The polycyclic heteroaryl group may be fused ornon-fused. The heteroatom(s) in the heteroaryl radical is optionallyoxidized. One or more nitrogen atoms, if present, are optionallyquaternized. The heteroaryl is attached to the rest of the moleculethrough any atom of the ring(s). Examples of heteroaryls include, butare not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl,1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl,benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl,1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl,benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl,pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e.thienyl). A heteroaryl moiety is unsubstituted or substituted.

The terms “aryl-alkyl”, “arylalkyl” and “aralkyl” are used to describe agroup wherein the alkyl chain can be branched or straight chain forminga linking portion with the terminal aryl, as defined above, of thearyl-alkyl moiety. Examples of aryl-alkyl groups include, but are notlimited to, optionally substituted benzyl, phenethyl, phenpropyl andphenbutyl such as 4-chlorobenzyl, 2,4-dibromobenzyl, 2-methylbenzyl,2-(3-fluorophenyl)ethyl, 2-(4-methylphenyl)ethyl,2-(4-(trifluoromethyl)phenyl)ethyl, 2-(2-methoxyphenyl)ethyl,2-(3-nitrophenyl)ethyl, 2-(2,4-dichlorophenyl)ethyl,2-(3,5-dimethoxyphenyl)ethyl, 3-phenylpropyl, 3-(3-chlorophenyl)propyl,3-(2-methylphenyl)propyl, 3-(4-methoxyphenyl)propyl,3-(4-(trifluoromethyl)phenyl)propyl, 3-(2,4-dichlorophenyl)propyl,4-phenylbutyl, 4-(4-chlorophenyl)butyl, 4-(2-methylphenyl)butyl,4-(2,4-dichlorophenyl)butyl, 4-(2-methoxphenyl)butyl, and10-phenyldecyl. Either portion of the moiety is unsubstituted orsubstituted.

The term “C₁₋₁₀alkylaryl” as used herein refers to an alkyl group, asdefined above, containing 1 to 10 carbon atoms, branched or unbranched,wherein the aryl group replaces one hydrogen on the alkyl group, forexample, 3-phenylpropyl. Either portion of the moiety is unsubstitutedor substituted.

The term C₂₋₁₀ alkyl monocycloaryl” refers to a group containing aterminal alkyl group, branched or straight chain and containing 2 to 10atoms attached to a linking aryl group which has only one ring, such asfor example, 2-phenyl ethyl. Either portion of the moiety isunsubstituted or substituted.

The term C₁₋₁₀ alkyl bicycloaryl” refers to a group containing aterminal alkyl group, branched or straight chain and containing 2 to 10atoms attached to a linking aryl group which is bicyclic, such as forexample, 2-(1-naphthyl)-ethyl. Either portion of the moiety isunsubstituted or substituted.

The terms “aryl-cycloalkyl” and “arylcycloalkyl” are used to describe agroup wherein the terminal aryl group is attached to a cycloalkyl group,for example phenylcyclopentyl and the like. Either portion of the moietyis unsubstituted or substituted.

The terms “hetaryl-C₃₋₈cycloalkyl” and “heteroaryl-C₃₋₈cycloalkyl” areused to describe a group wherein the terminal hetaryl group is attachedto a cycloalkyl group, which contains 3 to 8 carbons, for examplepyrid-2-yl-cyclopentyl and the like. Either portion of the moiety isunsubstituted or substituted.

The term “hetaryl-heteroalkyl” refers to a group wherein the terminalhetaryl group is attached to a linking heteroalkyl group, such as forexample, pyrid-2-yl methylenoxy, and the like. Either portion of themoiety is unsubstituted or substituted.

The terms “aryl-alkenyl”, “arylalkenyl” and “aralkenyl” are used todescribe a group wherein the alkenyl chain can be branched or straightchain forming a linking portion of the aralkenyl moiety with theterminal aryl portion, as defined above, for example styryl(2-phenylvinyl), phenpropenyl, and the like. Either portion of themoiety is unsubstituted or substituted.

The term “aryl-C₂₋₁₀alkenyl” means an arylalkenyl as described abovewherein the alkenyl moiety contains 2 to 10 carbon atoms such as forexample, styryl (2-phenylvinyl), and the like. Either portion of themoiety is unsubstituted or substituted.

The term “C₂₋₁₀alkenyl-aryl” is used to describe a group wherein theterminal alkenyl group, which contains 2 to 10 carbon atoms and can bebranched or straight chain, is attached to the aryl moiety which formsthe linking portion of the alkenyl-aryl moiety, such as for example,3-propenyl-naphth-1-yl, and the like. Either portion of the moiety isunsubstituted or substituted.

The terms “aryl-alkynyl”, “arylalkynyl” and “aralkynyl” are used todescribe a group wherein the alkynyl chain can be branched or straightchain forming a linking portion of the aryl-alkynyl moiety with theterminal aryl portion, as defined above, for example3-phenyl-1-propynyl, and the like. Either portion of the moiety isunsubstituted or substituted.

The term “aryl-C₂₋₁₀alkynyl” means an arylalkynyl as described abovewherein the alkynyl moiety contains two to ten carbons, such as, forexample 3-phenyl-1-propynyl, and the like . Either portion of the moietyis unsubstituted or substituted.

The term “C₂₋₁₀alkynyl-aryl” means a group containing an alkynyl moietyattached to an aryl linking group, both as defined above, wherein thealkynyl moiety contains two to ten carbons, such as, for example3-propynyl-naphth-1-yl. Either portion of the moiety is unsubstituted orsubstituted.

The terms “aryl-oxy”, “aryloxy” and “aroxy” are used to describe aterminal aryl group attached to a linking oxygen atom. Typical aryl-oxygroups include phenoxy, 3,4-dichlorophenoxy, and the like. Eitherportion of the moiety is unsubstituted or substituted.

The terms “aryl-oxyalkyl”, “aryloxyalkyl” and “aroxyalkyl” are used todescribe a group wherein an alkyl group is substituted with a terminalaryl-oxy group, for example pentafluorophenoxymethyl and the like.Either portion of the moiety is unsubstituted or substituted.

The term “C₁₋₁₀alkoxy-C₁₋₁₀alkyl” refers to a group wherein an alkoxygroup, containing 1 to 10 carbon atoms and an oxygen atom within thebranching or straight chain, is attached to a linking alkyl group,branched or straight chain which contains 1 to 10 carbon atoms, such as,for example methoxypropyl, and the like. Either portion of the moiety isunsubstituted or substituted.

The term “C₁₋₁₀alkoxy-C₂₋₁₀alkenyl” refers to a group wherein an alkoxygroup, containing 1 to 10 carbon atoms and an oxygen atom within thebranching or straight chain, is attached to a linking alkenyl group,branched or straight chain which contains 1 to 10 carbon atoms, such as,for example 3-methoxybut-2-en-1-yl, and the like. Either portion of themoiety is unsubstituted or substituted.

The term “C₁₋₁₀alkoxy-C₂₋₁₀alkynyl” refers to a group wherein an alkoxygroup, containing 1 to 10 carbon atoms and an oxygen atom within thebranching or straight chain, is attached to a linking alkynyl group,branched or straight chain which contains 1 to 10 carbon atoms, such as,for example 3-methoxybut-2-in-1-yl, and the like. Either portion of themoiety is unsubstituted or substituted.

The term “heterocycloalkenyl” refers to a cycloalkenyl structure, whichis unsubstituted or substituted in which at least one carbon atom isreplaced with a heteroatom selected from oxygen, nitrogen, and sulfur.

The terms “hetaryl-oxy”, “heteroaryl-oxy”, “hetaryloxy”,“heteroaryloxy”, “hetaroxy” and “heteroaroxy” are used to describe aterminal hetaryl group, which is unsubstituted or substituted, attachedto a linking oxygen atom. Typical hetaryl-oxy groups include4,6-dimethoxypyrimidin-2-yloxy and the like.

The terms “hetarylalkyl”, “heteroarylalkyl”, “hetaryl-alkyl”,“heteroaryl-alkyl”, “hetaralkyl” and “heteroaralkyl” are used todescribe a group wherein the alkyl chain can be branched or straightchain forming a linking portion of the heteroaralkyl moiety with theterminal heteroaryl portion, as defined above, for example3-furylmethyl, thenyl, furfuryl, and the like. Either portion of themoiety is unsubstituted or substituted.

The term “hetaryl-C₁₋₁₀alkyl” is used to describe a hetaryl alkyl groupas described above where the alkyl group contains 1 to 10 carbon atoms.Either portion of the moiety is unsubstituted or substituted.

The term “C₁₋₁₀alkyl-hetaryl” is used to describe a alkyl attached to ahetaryl group as described above where the alkyl group contains 1 to 10carbon atoms. Either portion of the moiety is unsubstituted orsubstituted.

The terms “hetarylalkenyl”, “heteroarylalkenyl”, “hetaryl-alkenyl”,“heteroaryl-alkenyl”, “hetaralkenyl” and “heteroaralkenyl” are used todescribe a hetarylalkenyl group wherein the alkenyl chain can bebranched or straight chain forming a linking portion of theheteroaralkenyl moiety with the terminal heteroaryl portion, as definedabove, for example 3-(4-pyridyl)-1-propenyl. Either portion of themoiety is unsubstituted or substituted.

The term “hetaryl-C₂₋₁₀alkenyl” group is used to describe a group asdescribed above wherein the alkenyl group contains 2 to 10 carbon atoms.Either portion of the moiety is unsubstituted or substituted.

The term “C₂₋₁₀alkenyl-hetaryl” is used to describe a group containingan alkenyl group, which is branched or straight chain and contains 2 to10 carbon atoms, and is attached to a linking hetaryl group, such as,for example 2-styryl-4-pyridyl, and the like. Either portion of themoiety is unsubstituted or substituted.

The terms “hetarylalkynyl”, “heteroarylalkynyl”, “hetaryl-alkynyl”,“heteroaryl-alkynyl”, “hetaralkynyl” and “heteroaralkynyl” are used todescribe a group wherein the alkynyl chain can be branched or straightchain forming a linking portion of the heteroaralkynyl moiety with theheteroaryl portion, as defined above, for example4-(2-thienyl)-1-butynyl, and the like. Either portion of the moiety isunsubstituted or substituted.

The term “hetaryl-C₂₋₁₀alkynyl” is used to describe a hetarylalkynylgroup as described above wherein the alkynyl group contains 2 to 10carbon atoms. Either portion of the moiety is unsubstituted orsubstituted.

The term “C₂₋₁₀alkynyl-hetaryl” is used to describe a group containingan alkynyl group which contains 2 to 10 carbon atoms and is branched orstraight chain, which is attached to a linking hetaryl group such as,for example, 4(but-1-ynyl)thien-2-yl, and the like. Either portion ofthe moiety is unsubstituted or substituted.

The term “heterocyclyl”, “hetcyclyl”, or “heterocycloalkyl” refers to asubstituted or unsubstituted 3-, 4-, 5-, or 6-membered saturated orpartially unsaturated ring containing one, two, or three heteroatoms,preferably one or two heteroatoms independently selected from oxygen,nitrogen and sulfur; or to a bicyclic ring system containing up to 10atoms including at least one heteroatom independently selected fromoxygen, nitrogen, and sulfur wherein the ring containing the heteroatomis saturated. Examples of heterocyclyls include, but are not limited to,tetrahydrofuranyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl,4-pyranyl, tetrahydropyranyl, thiolanyl, morpholinyl, piperazinyl,dioxolanyl, dioxanyl, indolinyl, and 5-methyl-6-chromanyl.

The terms “heterocyclylalkyl”, “heterocyclyl-alkyl”, “hetcyclylalkyl”,and “hetcyclyl-alkyl” are used to describe a group wherein the alkylchain can be branched or straight chain forming a linking portion of theheterocyclylalkyl moiety with the terminal heterocyclyl portion, asdefined above, for example 3-piperidinylmethyl and the like. The term“heterocycloalkylene” refers to the divalent derivative ofheterocycloalkyl.

The term “C₁₋₁₀alkyl-heterocycyl” refers to a group as defined abovewhere the alkyl moiety contains 1 to 10 carbon atoms. Either portion ofthe moiety is unsubstituted or substituted.

The term “heterocycyl-C₁₋₁₀alkyl” refers to a group containing aterminal heterocyclic group attached to a linking alkyl group whichcontains 1 to 10 carbons and is branched or straight chain, such as, forexample, 4-morpholinyl ethyl, and the like. Either portion of the moietyis unsubstituted or substituted.

The terms “heterocyclylalkenyl”, “heterocyclyl-alkenyl”,“hetcyclylalkenyl” and “hetcyclyl-alkenyl” are used to describe a groupwherein the alkenyl chain can be branched or straight chain forming alinking portion of the heterocyclylalkenyl moiety with the terminalheterocyclyl portion, as defined above, for example2-morpholinyl-1-propenyl and the like. The term “heterocycloalkenylene”refers to the divalent derivative of heterocyclylalkenyl. Either portionof the moiety is unsubstituted or substituted.

The term “heterocycyl-C₂₋₁₀ alkenyl” refers to a group as defined abovewhere the alkenyl group contains 2 to 10 carbon atoms and is branched orstraight chain, such as, for example, 4-(N-piperazinyl)-but-2-en-1-yl,and the like. Either portion of the moiety is unsubstituted orsubstituted.

The terms “heterocyclylalkynyl”, “heterocyclyl-alkynyl”,“hetcyclylalkynyl” and “hetcyclyl-alkynyl” are used to describe a groupwherein the alkynyl chain can be branched or straight chain forming alinking portion of the heterocyclylalkynyl moiety with the terminalheterocyclyl portion, as defined above, for example2-pyrrolidinyl-1-butynyl and the like. Either portion of the moiety isunsubstituted or substituted.

The term “heterocycyl-C₂₋₁₀ alkynyl” refers to a group as defined abovewhere the alkynyl group contains 2 to 10 carbon atoms and is branched orstraight chain, such as, for example, 4-(N-piperazinyl)-but-2-yn-1-yl,and the like.

The term “aryl-heterocycyl” refers to a group containing a terminal arylgroup attached to a linking heterocyclic group, such as for example,N4-(4-phenyl)-piperazinyl, and the like. Either portion of the moiety isunsubstituted or substituted.

The term “hetaryl-heterocycyl” refers to a group containing a terminalhetaryl group attached to a linking heterocyclic group, such as forexample, N4-(4-pyridyl)-piperazinyl, and the like. Either portion of themoiety is unsubstituted or substituted.

The term “carboxylalkyl” refers to a terminal carboxyl (—COOH) groupattached to branched or straight chain alkyl groups as defined above.

The term “carboxylalkenyl” refers to a terminal carboxyl (—COOH) groupattached to branched or straight chain alkenyl groups as defined above.

The term “carboxylalkynyl” refers to a terminal carboxyl (—COOH) groupattached to branched or straight chain alkynyl groups as defined above.

The term “carboxylcycloalkyl” refers to a terminal carboxyl (—COOH)group attached to a cyclic aliphatic ring structure as defined above.

The term “carboxylcycloalkenyl” refers to a terminal carboxyl (—COOH)group attached to a cyclic aliphatic ring structure having ethylenicbonds as defined above.

The terms “cycloalkylalkyl” and “cycloalkyl-alkyl” refer to a terminalcycloalkyl group as defined above attached to an alkyl group, forexample cyclopropylmethyl, cyclohexylethyl, and the like. Either portionof the moiety is unsubstituted or substituted.

The terms “cycloalkylalkenyl” and “cycloalkyl-alkenyl” refer to aterminal cycloalkyl group as defined above attached to an alkenyl group,for example cyclohexylvinyl, cycloheptylallyl, and the like. Eitherportion of the moiety is unsubstituted or substituted.

The terms “cycloalkylalkynyl” and “cycloalkyl-alkynyl” refer to aterminal cycloalkyl group as defined above attached to an alkynyl group,for example cyclopropylpropargyl, 4-cyclopentyl-2-butynyl, and the like.Either portion of the moiety is unsubstituted or substituted.

The terms “cycloalkenylalkyl” and “cycloalkenyl-alkyl” refer to aterminal cycloalkenyl group as defined above attached to an alkyl group,for example 2-(cyclopenten-1-yl)ethyl and the like. Either portion ofthe moiety is unsubstituted or substituted.

The terms “cycloalkenylalkenyl” and “cycloalkenyl-alkenyl” refer toterminal a cycloalkenyl group as defined above attached to an alkenylgroup, for example 1-(cyclohexen-3-yl)allyl and the like.

The terms “cycloalkenylalkynyl” and “cycloalkenyl-alkynyl” refer toterminal a cycloalkenyl group as defined above attached to an alkynylgroup, for example 1-(cyclohexen-3-yl)propargyl and the like. Eitherportion of the moiety is unsubstituted or substituted.

The term “alkoxy” includes both branched and straight chain terminalalkyl groups attached to a linking oxygen atom. Typical alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy and thelike. An alkoxy moiety is unsubstituted or substituted.

The term “haloalkoxy” refers to an alkoxy group substituted with one ormore halo groups, for example chloromethoxy, trifluoromethoxy,difluoromethoxy, perfluoroisobutoxy, and the like.

The term “alkoxyalkoxyalkyl” refers to an alkyl group substituted withan alkoxy moiety which is in turn is substituted with a second alkoxymoiety, for example methoxymethoxymethyl, isopropoxymethoxyethyl, andthe like. This moiety is substituted with further substituents or notsubstituted with other substituents.

The term “alkylthio” includes both branched and straight chain alkylgroups attached to a linking sulfur atom, for example methylthio and thelike.

The term “alkoxyalkyl” refers to an alkyl group substituted with analkoxy group, for example isopropoxymethyl and the like. Either portionof the moiety is unsubstituted or substituted.

The term “alkoxyalkenyl” refers to an alkenyl group substituted with analkoxy group, for example 3-methoxyallyl and the like. Either portion ofthe moiety is unsubstituted or substituted.

The term “alkoxyalkynyl” refers to an alkynyl group substituted with analkoxy group, for example 3-methoxypropargyl and the like. Eitherportion of the moiety is unsubstituted or substituted.

The term “C₂₋₁₀alkenylC₃₋₈cycloalkyl” refers to an alkenyl group asdefined above substituted with a three to eight membered cycloalkylgroup, for example, 4-(cyclopropyl)-2-butenyl and the like. Eitherportion of the moiety is unsubstituted or substituted.

The term “C₂₋₁₀alkynylC₃₋₈cycloalkyl” refers to an alkynyl group asdefined above substituted with a three to eight membered cycloalkylgroup, for example, 4-(cyclopropyl)-2-butynyl and the like. Eitherportion of the moiety is unsubstituted or substituted.

The term “heterocyclyl-C₁₋₁₀alkyl” refers to a heterocyclic group asdefined above substituted with an alkyl group as defined above having 1to 10 carbons, for example, 4-(N-methyl)-piperazinyl, and the like.Either portion of the moiety is unsubstituted or substituted.

The term “heterocyclyl-C₂₋₁₀alkenyl” refers to a heterocyclic group asdefined above, substituted with an alkenyl group as defined above,having 2 to 10 carbons, for example, 4-(N-allyl)piperazinyl, and thelike. Moieties wherein the heterocyclic group is substituted on a carbonatom with an alkenyl group are also included. Either portion of themoiety is unsubstituted or substituted.

The term “heterocyclyl-C₂₋₁₀alkynyl” refers to a heterocyclic group asdefined above, substituted with an alkynyl group as defined above,having 2 to 10 carbons, for example, 4-(N-propargyl)piperazinyl, and thelike. Moieties wherein the heterocyclic group is substituted on a carbonatom with an alkenyl group are also included. Either portion of themoiety is unsubstituted or substituted.

The term “oxo” refers to an oxygen that is double bonded to a carbonatom. One in the art understands that an “oxo” requires a second bondfrom the atom to which the oxo is attached. Accordingly, it isunderstood that oxo cannot be subststituted onto an aryl or heteroarylring, unless it forms part of the aromatic system as a tautomer.

The term “oligomer” refers to a low-molecular weight polymer, whosenumber average molecular weight is typically less than about 5000 g/mol,and whose degree of polymerization (average number of monomer units perchain) is greater than one and typically equal to or less than about 50.

“Sulfonamidyl” or “sulfonamido” refers to a —S(═O)₂—NR′R′ radical, whereeach R′ is selected independently from the group consisting of hydrogen,alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheteroalicyclic (bonded through a ring carbon). The R′groups in —NR′R′of the —S(═O)₂—NR′R′ radical may be taken together with the nitrogen towhich it is attached to form a 4-, 5-, 6-, or 7-membered ring. Asulfonamido group is optionally substituted by one or more of thesubstituents described for alkyl, cycloalkyl, aryl, heteroarylrespectively.

Compounds described can contain one or more asymmetric centers and maythus give rise to diastereomers and optical isomers. The presentinvention includes all such possible diastereomers as well as theirracemic mixtures, their substantially pure resolved enantiomers, allpossible geometric isomers, and pharmaceutically acceptable saltsthereof. The above Formula I is shown without a definitivestereochemistry at certain positions. The present invention includes allstereoisomers of Formula I and pharmaceutically acceptable saltsthereof. Further, mixtures of stereoisomers as well as isolated specificstereoisomers are also included. During the course of the syntheticprocedures used to prepare such compounds, or in using racemization orepimerization procedures known to those skilled in the art, the productsof such procedures can be a mixture of stereoisomers.

The present invention includes all manner of rotamers andconformationally restricted states of a compound of the invention.

Substituents for alkyl, heteroalkyl, cycloalkyl, heterocycloalkylmonovalent and divalent derivative radicals (including those groupsoften referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl,alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to: alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen,—SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —C(O)NR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)OR, —NR—C(NR′R″)═NR′″, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN and —NO₂ in a number ranging fromzero to (2m′+1), where m′ is the total number of carbon atoms in suchradical. R′, R″, R′″ and R″″ each preferably independently refer tohydrogen, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl (e.g., aryl substituted with 1-3halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxygroups, or arylalkyl groups. When a compound of the invention includesmore than one R group, for example, each of the R groups isindependently selected as are each R′, R″, R′″ and R″″ groups when morethan one of these groups is present.

When R′ and R″ or R″ and R′″ are attached to the same nitrogen atom,they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or7-membered ring. For example, —NR′R″ is meant to include, but not belimited to, 1-pyrrolidinyl, 4 piperazinyl, and 4-morpholinyl. From theabove discussion of substituents, one of skill in the art willunderstand that the term “alkyl” is meant to include groups includingcarbon atoms bound to groups other than hydrogen groups, such ashaloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃,—C(O)CH₂OCH₃, and the like).

Similar to the substituents described for alkyl radicals above,exemplary substituents for aryl and heteroaryl groups (as well as theirdivalent derivatives) are varied and are selected from, for example:halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —OR′,—NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′,—C(O)NR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)OR,—NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″,—NRSO₂R′, —CN and —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxo, andfluoro(C₁-C₄)alkyl, in a number ranging from zero to the total number ofopen valences on aromatic ring system; and where R′, R″, R′″ and R″″ arepreferably independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl. When a compound of the invention includes morethan one R group, for example, each of the R groups is independentlyselected as are each R′, R″, R′″ and R″″ groups when more than one ofthese groups is present.

As used herein, 0-2 in the context of —S(O)₍₀₋₂₎— are integers of 0, 1,and 2.

Two of the substituents on adjacent atoms of aryl or heteroaryl ring mayoptionally form a ring of the formula -T-C(O)—(CRR′)_(q)-U-, wherein Tand U are independently —NR—, —O—, —CRR′— or a single bond, and q is aninteger of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -A-(CH₂)_(r)-B-, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CRR′)_(s)—X′—(C″R′″)_(d)—, where s and d are independentlyintegers of from 0 to 3, and X¹ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″ and R′″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl.

A. Generic Formulas and Detailed Description

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C— or ¹⁴C-enriched carbonare within the scope of this invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of atoms that constitutesuch compounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds ofthe present invention, whether radioactive or not, are encompassedwithin the scope of the present invention.

A compound or a pharmaceutically acceptable salt thereof is provided,wherein the compound has the Formula I′-A′:

or a pharmaceutically acceptable salt thereof, wherein:

X₁ is N or C-E¹, X₂ is N, X₃ is C, and X₄ is C—R⁹ or N; or X₁ is N orC-E¹, X₂ is C, X₃ is N, and X₄ is C—R⁹ or N;

wherein no more than two nitrogen ring atoms are adjacent;

R₁ is —H, -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl,-L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl, -L-aryl, -L-heteroaryl, -L-C₁₋₁₀alkylaryl,-L-C₁₋₁₀alkylhetaryl, -L-C₁₋₁₀alkylheterocylyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₂₋₁₀alkenyl-C₃₋₈cycloalkyl,-L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl, -L-heteroalkyl, -L-heteroalkylaryl,-L-heteroalkylheteroaryl, -L-heteroalkyl-heterocylyl,-L-heteroalkyl-C₃₋₈cycloalkyl, -L-aralkyl, -L-heteroaralkyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

M₁ is a moiety having the structure of Formula A-1 or Formula A-2:

k is 0 or 1;

E¹ and E² are independently -(W¹)_(j)-R⁴;

j, in each instance (i.e., in E¹ or j in E²), is independently 0 or 1

W¹ is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)S(O)—, —N(R⁷)S(O)₂, —C(O)O—, —CH(R⁷)N(C(O)OR⁸)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—;

W² is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)C(O)N(R⁸)—, —N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—,—CH(R⁷)N(C(O)OR⁸)—, —CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—,—CH(R⁷)C(O)N(R⁸)—, —CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or—CH(R⁷)N(R⁸)S(O)₂—;

R² is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,aryl (e.g. bicyclic aryl, unsubstituted aryl, or substituted monocyclicaryl), hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl,C₃₋₈cycloalkyl-C₁₋₁₀alkyl, C₃₋₈cycloalkyl-C₂₋₁₀alkenyl,C₃₋₈cycloalkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkyl-C₂₋₁₀alkenyl,C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl (e.g. C₂₋₁₀alkyl-monocyclicaryl, C₁₋₁₀alkyl-substituted monocyclic aryl, or C₁₋₁₀alkylbicycloaryl),C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl,C₂₋₁₀alkynylheteroalkyl, C₂₋₁₀alkynylheterocylyl,C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxy C₁₋₁₀alkyl,C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl, heterocyclyl,heteroalkyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl (e.g. monocyclicaryl-C₂₋₁₀alkyl, substituted monocyclic aryl-C₁₋₁₀alkyl, orbicycloaryl-C₁₋₁₀alkyl), aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl,hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl, hetaryl-heteroalkyl, orhetaryl heterocyclyl, wherein each of said bicyclic aryl or heteroarylmoiety is unsubstituted, or wherein each of bicyclic aryl, heteroarylmoiety or monocyclic aryl moiety is substituted with one or moreindependent alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo,—OH, —R³¹, —CF₃, —OCF₃, —OR³¹, NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³²,—SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³,NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³²,—NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³²,—OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³², and whereineach of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety isunsubstituted or is substituted with one or more alkyl, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—O-aryl, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, C(═O)NR³⁴R³⁵, or(═O)NR³¹R³²;

R³ and R⁴ are independently hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³², aryl, hetaryl, C₁₋₄alkyl,C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl,C₃₋₈cycloalkyl-C₁₋₁₀alkyl, C₃₋₈cycloalkyl-C₂₋₁₀alkenyl,C₃₋₈cycloalkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkyl-C₂₋₁₀alkenyl,C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl, C₁₋₁₀alkylhetaryl,C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl,heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl,heteroalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein eachof said aryl or heteroaryl moiety is unsubstituted or is substitutedwith one or more independent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵,—NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R, or —C(═O)NR³¹R³²;

R⁵ is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³²;

R³¹, R³², and R³³, in each instance, are independently H or C₁₋₁₀alkyl,wherein the C₁₋₁₀alkyl is unsubstituted or is substituted with one ormore aryl, heteroalkyl, heterocyclyl, or hetaryl group, wherein each ofsaid aryl, heteroalkyl, heterocyclyl, or hetaryl group is unsubstitutedor is substituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃,—O-aryl, —OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl),—NH(C₁₋₁₀alkyl), —NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl),—C(O)(C₁₋₁₀alkyl-aryl), —C(O)(aryl), —CO₂—C₁₋₁₀alkyl,—CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl, —C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl),—C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵, —C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl),—O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂aryl, —SO₂N(aryl),—SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or SO₂NR³⁴R³⁵;

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen atom;

R⁷ and R⁸ are each independently hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,aryl, heteroaryl, heterocyclyl or C₃₋₁₀cycloalkyl, each of which exceptfor hydrogen is unsubstituted or is substituted by one or moreindependent R⁶;

R⁶ is halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl; aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, whereineach of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl,or hetaryl group is unsubstituted or is substituted with one or moreindependent halo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², or—NR³⁴R³⁵; and

R⁹ is H, halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl; aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, whereineach of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl,or hetaryl group is unsubstituted or is substituted with one or moreindependent halo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², or—NR³⁴R³⁵.

In some embodiments, X₄ is C—R⁹.

The invention also provides a compound as defined above, wherein thecompound is of Formula I:

or a pharmaceutically acceptable salt thereof, and wherein thesubstituents are as defined above.

In various embodiments the compound of Formula I or its pharmaceuticallyacceptable salt thereof, is a compound having the structure of FormulaI-A or Formula I-B:

or a pharmaceutically acceptable salt thereof.

In various embodiments of Formula I-A, X₁ is N and X₂ is N. In otherembodiments, X₁ is C-E¹ and X₂ is N. In yet other embodiments, X₁ is NHand X₂ is C. In further embodiments, X₁ is CH-E¹ and X₂ is C.

In various embodiments of Formula I-B, X₁ is N and X₂ is C. In furtherembodiments, X₁ is C-E¹ and X₂ is C.

In various embodiments, X₁ is C-(W¹)_(j)-R⁴, where j is 0.

In another embodiment, X₁ is CH. In yet another embodiment, X₁ isC-halogen, where halogen is Cl, F, Br, or I.

In various embodiments of X₁, it is C-(W¹)_(j)-R⁴. In variousembodiments of X₁, j is 1, and W¹ is —O—. In various embodiments of X₁,j is 1, and W¹ is —NR⁷—. In various embodiments of X₁, j is 1, and W¹ is—NH—. In various embodiments of X₁, j is 1, and W¹ is —S(O)₀₋₂—. Invarious embodiments of X₁, j is 1, and W¹ is —C(O)—. In variousembodiments of X₁, j is 1, and W¹ is —C(O)N(R⁷)—. In various embodimentsof X₁, j is 1, and W¹ is —N(R⁷)C(O)—. In various embodiments of X₁, j is1, and W¹ is —N(R⁷)S(O)—. In various embodiments of X₁, j is 1, and W¹is —N(R⁷)S(O)₂—. In various embodiments of X₁, j is 1, and W¹ is—C(O)O—. In various embodiments of X₁, j is 1, and W¹ isCH(R⁷)N(C(O)OR)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)N(C(O)R)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)N(SO₂R)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)N(R⁸)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)C(O)N(R⁸)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)N(R⁸)C(O)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)N(R⁸)S(O)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)N(R⁸)S(O)₂—.

In various embodiments, X₁ is CH-(W¹)_(j)-R⁴, where j is 0.

In another embodiment, X₁ is CH₂. In yet another embodiment, X₁ isCH-halogen, where halogen is Cl, F, Br, or I.

In various embodiments of X₁, it is CH-(W¹)_(j)-R⁴. In variousembodiments of X₁, j is 1, and W¹ is —O—. In various embodiments of X₁,j is 1, and W¹ is —NR⁷—. In various embodiments of X₁, j is 1, and W¹ is—NH—. In various embodiments of X₁, j is 1, and W¹ is —S(O)₀₋₂—. Invarious embodiments of X₁, j is 1, and W¹ is —C(O)—. In variousembodiments of X₁, j is 1, and W¹ is —C(O)N(R⁷)—. In various embodimentsof X₁, j is 1, and W¹ is —N(R⁷)C(O)—. In various embodiments of X₁, j is1, and W¹ is —N(R⁷)S(O)—. In various embodiments of X₁, j is 1, and W¹is —N(R⁷)S(O)₂—. In various embodiments of X₁, j is 1, and W¹ is—C(O)O—. In various embodiments of X₁, j is 1, and W¹ isCH(R⁷)N(C(O)OR)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)N(C(O)R)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)N(SO₂R)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)N(R⁸)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)C(O)N(R⁸)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)N(R⁸)C(O)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)N(R⁸)S(O)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)N(R⁸)S(O)₂—.

In another embodiment, X₁ is N.

In various embodiments, X₂ is N. In other embodiments, X₂ is C.

In various embodiments, E² is -(W¹)_(j)-R⁴, where j is 0.

In another embodiment, E² is CH. In yet another embodiment, E² isC-halogen, where halogen is Cl, F, Br, or I.

In various embodiments of E², it is -(W¹)_(j)-R⁴. In various embodimentsof E², j is 1, and W¹ is —O—. In various embodiments of E², j is 1, andW¹ is —NR⁷—. In various embodiments of E², j is 1, and W¹ is —NH—. Invarious embodiments of E², j is 1, and W¹ is —S(O)₀₋₂—. In variousembodiments of E², j is 1, and W¹ is —C(O)—. In various embodiments ofE², j is 1, and W¹ is —C(O)N(R⁷)—. In various embodiments of E², j is 1,and W¹ is —N(R⁷)C(O)—. In various embodiments of E², j is 1, and W¹ is—N(R⁷)S(O)—. In various embodiments of E², j is 1, and W¹ is—N(R⁷)S(O)₂—. In various embodiments of E², j is 1, and W¹ is —C(O)O—.In various embodiments of E², j is 1, and W¹ is CH(R⁷)N(C(O)OR)—. Invarious embodiments of E², j is 1, and W¹ is —CH(R⁷)N(C(O)R)—. Invarious embodiments of E², j is 1, and W¹ is —CH(R⁷)N(SO₂R)—. In variousembodiments of E², j is 1, and W¹ is —CH(R⁷)N(R⁸)—. In variousembodiments of E², j is 1, and W¹ is —CH(R⁷)C(O)N(R⁸)—. In variousembodiments of E², j is 1, and W¹ is —CH(R⁷)N(R⁸)C(O)—. In variousembodiments of E², j is 1, and W¹ is —CH(R⁷)N(R⁸)S(O)—. In variousembodiments of E², j is 1, and W¹ is —CH(R⁷)N(R⁸)S(O)₂—.

In various embodiments when M₁ is a moiety of Formula A-1, M₁ isbenzoxazolyl substituted with -(W₂)_(k)-R₂. In some embodiments, M₁ is abenzoxazolyl substituted at the 2-position with -(W²)_(j)-R². In someembodiments, M₁ is either a 5-benzoxazolyl or a 6-benzoxazolyl moiety,optionally substituted at the 2-position with -(W²)_(j)-R². ExemplaryFormula A-I M₁ moieties include but are not limited to the following:

In various embodiments when M₁ is a moiety of Formula A-2, Formula A-2is an aza-substituted benzoxazolyl moiety having a structure of one ofthe following formulae:

Exemplary Formula A-2 M₁ moieties include but are not limited to thefollowing:

In various embodiments of M₁, k is 0. In other embodiments of M₁, k is1, and W² is selected from one of the following: —O—, —NR⁷—, —S(O)₀₋₂—,—C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—, or —N(R⁷)C(O)N(R⁸)—. In yet anotherembodiment of M₁, k is 1, and W² is —N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—,—CH(R⁷)N(C(O)OR⁸)—, —CH(R⁷)N(C(O)R⁸)—, or —CH(R⁷)N(SO₂R⁸⁾—. In a furtherembodiment of M₁, k is 1, and W² is —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, or —CH(R⁷)N(R⁸)S(O)—. In yet another embodiment ofM₁, k is 1, and W² is —CH(R⁷)N(R⁸)S(O)₂—.

In some embodiments, the compound of Formula Formula I′-A′, I (includingI-A and I-B), II-A (including II-A-1 and II-A-2), II-B (including II-B-1and II-B-2), C, 3-6, C″, or 3-6′″ is not a compound having one of thefollowing structures:

The invention provides a compound of Formula II-A or Formula II-B:

or a pharmaceutically acceptable salt thereof, wherein X₁ is N or C-E¹,X₂ is N, and X₃ is C; or X₁ is N or C-E¹, X₂ is C₁ and X₃ is N;

R₁ is H, -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl,-L-aryl, -L-heteroaryl, -L-C₁₋₁₀alkylaryl, -L-C₁₋₁₀alkylhetaryl,-L-C₁₋₁₀alkylheterocylyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl,-L-C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, -L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,-L-heteroalkyl, -L-heteroalkylaryl, -L-heteroalkylheteroaryl,-L-heteroalkyl-heterocylyl, -L-heteroalkyl-C₃₋₈cycloalkyl, -L-aralkyl,-L-heteroaralkyl, or -L-heterocyclyl, each of which is unsubstituted oris substituted by one or more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

E¹ and E² are independently -(W¹)_(j)-R⁴;

j in E¹ or j in E², is independently 0 or 1;

W¹ is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)S(O)—, —N(R⁷)S(O)₂, —C(O)O—, —CH(R⁷)N(C(O)OR⁸)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—;

W² is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)C(O)N(R⁸), —N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—, —CH(R⁷)N(C(O)OR⁸)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—;

k is 0 or 1;

R² is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,aryl (e.g. bicyclic aryl, unsubstituted aryl, or substituted monocyclicaryl), hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl,C₃₋₈cycloalkyl-C₁₋₁₀alkyl, C₃₋₈cycloalkyl-C₂₋₁₀alkenyl,C₃₋₈cycloalkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkyl-C₂₋₁₀alkenyl,C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl (e.g. C₂₋₁₀alkyl-monocyclicaryl, C₁₋₁₀alkyl-substituted monocyclic aryl, or C₁₋₁₀alkylbicycloaryl),C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl,C₂₋₁₀alkynylheteroalkyl, C₂₋₁₀alkynylheterocylyl,C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxy C₁₋₁₀alkyl,C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl,heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl (e.g. monocyclicaryl-C₂₋₁₀alkyl, substituted monocyclic aryl-C₁₋₁₀alkyl, orbicycloaryl-C₁₋₁₀alkyl), aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl,hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl, hetaryl-heteroalkyl, orhetaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroarylmoiety is unsubstituted, or wherein each of bicyclic aryl, heteroarylmoiety or monocyclic aryl moiety is substituted with one or moreindependent alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo,—OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³²,—SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³,—NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³²,—NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³²,—OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³² s, andwherein each of said alkyl, cycloalkyl, heterocyclyl, or heteroalkylmoiety is unsubstituted or is substituted with one or more alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —O-aryl, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or—C(═O)NR³¹R³²;

R³ and R⁴ are independently hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³², aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₁₋₁₀alkyl-C₂₋₁₀alkenyl, C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl,C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl,C₂₋₁₀alkynylheteroalkyl, C₂₋₁₀alkynylheterocylyl,C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxy C₁₋₁₀alkyl,C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl,heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl,hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein each of said arylor heteroaryl moiety is unsubstituted or is substituted with one or moreindependent alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo,—OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³²,—SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³,—NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³²,—NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³²,—OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³², and whereineach of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety isunsubstituted or is substituted with one or more alkyl, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—O-aryl, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or—C(═O)NR³¹R³²;

R⁵ is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³²;

R³¹, R³², and R³³, in each instance, are independently H or C₁₋₁₀alkyl,wherein the C₁₋₁₀alkyl is unsubstituted or is substituted with one ormore aryl, heteroalkyl, heterocyclyl, or hetaryl group, wherein each ofsaid aryl, heteroalkyl, heterocyclyl, or hetaryl group is unsubstitutedor is substituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃,—O-aryl, —OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl),—NH(C₁₋₁₀alkyl), —NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl),—C(O)(C₁₋₁₀alkyl-aryl), —C(O)(aryl), —CO₂—C₁₋₁₀alkyl,—CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl, —C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl),—C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵, —C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl),—O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂aryl, —SO₂N(aryl),—SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or —SO₂NR³⁴R³⁵;

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen atom; and

R⁷ and R⁸ are each independently hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,aryl, heteroaryl, heterocyclyl or C₃₋₁₀cycloalkyl, each of which exceptfor hydrogen is unsubstituted or is substituted by one or moreindependent R⁶; and R⁶ is halo, —OR³¹SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³²,—CO₂R³¹, —CO₂aryl, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₀₋₂C₁₋₁₀alkyl, S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl,C₂₋₁₀alkenyl, or C₂₋₁₀alkynyl; or R⁶ is aryl-C₁₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, each of which isunsubstituted or is substituted with one or more independent halo,cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², orNR³⁴R³⁵.

In various embodiments of the compound of Formula II-A, the compound hasa structure of Formula II-A-1 or Formula II-A-2:

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula II-A-1, X₁ is N and X₂ is N. In otherembodiments, X₁ is C-E¹ and X₂ is N. In yet other embodiments, X₁ is NHand X₂ is C. In further embodiments, X₁ is CH-E¹ and X₂ is C.

In several embodiments of Formula II-A-2, X₁ is N and X₂ is C. In yetother embodiments, X₁ is NH and X₂ is C. In further embodiments, X₁ isCH-E¹ and X₂ is C.

In various embodiments of the compound of Formula II-B, the compound hasa structure of Formula II-B-1 or Formula II-B-2:

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula II-B-1, X₁ is N and X₂ is N. In otherembodiments, X₁ is C-E¹ and X₂ is N. In yet other embodiments, X₁ is NHand X₂ is C. In further embodiments, X₁ is CH-E¹ and X₂ is C.

In several embodiments of Formula II-B-2, X₁ is N and X₂ is C. Infurther embodiments, X₁ is C-E¹ and X₂ is C.

In various embodiments, X₁ is C-(W¹)_(j)-R⁴, where j is 0.

In another embodiment, X₁ is CH. In yet another embodiment, X₁ isC-halogen, where halogen is Cl, F, Br, or I.

In various embodiments of X₁, it is C-(W¹)_(j)-R⁴. In variousembodiments of X₁, j is 1, and W¹ is —O—. In various embodiments of X₁,j is 1, and W¹ is —NR⁷—. In various embodiments of X₁, j is 1, and W¹ is—NH—. In various embodiments of X₁, j is 1, and W¹ is —S(O)₀₋₂. Invarious embodiments of X₁, j is 1, and W¹ is —C(O)—. In variousembodiments of X₁, j is 1, and W¹ is —C(O)N(R⁷). In various embodimentsof X₁, j is 1, and W¹ is —N(R⁷)C(O). In various embodiments of X₁, j is1, and W¹ is —N(R⁷)S(O). In various embodiments of X₁, j is 1, and W¹ is—N(R⁷)S(O)₂—. In various embodiments of X₁, j is 1, and W¹ is —C(O)O—.In various embodiments of X₁, j is 1, and W¹ is CH(R⁷)N(C(O)OR⁸)—. Invarious embodiments of X₁, j is 1, and W¹ is —CH(R⁷)N(C(O)R⁸)—. Invarious embodiments of X₁, j is 1, and W¹ is —CH(R⁷)N(SO₂R)—. In variousembodiments of X₁, j is 1, and W¹ is —CH(R⁷)N(R⁸)—. In variousembodiments of X₁, j is 1, and W¹ is —CH(R⁷)C(O)N(R⁸)—. In variousembodiments of X₁, j is 1, and W¹ is —CH(R⁷)N(R⁸)C(O)—. In variousembodiments of X₁, j is 1, and —W¹ is —CH(R⁷)N(R⁸)S(O)—. In variousembodiments of X₁, j is 1, and W¹ is —CH(R⁷)N(R⁸)S(O)₂—.

In various embodiments, X₁ is CH-(W¹)_(j)-R⁴, where j is 0.

In another embodiment, X₁ is CH₂. In yet another embodiment, X₁ isCH-halogen, where halogen is Cl, F, Br, or I.

In various embodiments of X₁, it is CH-(W¹)_(j)-R⁴. In variousembodiments of X₁, j is 1, and W¹ is —O—. In various embodiments of X₁,j is 1, and W¹ is —NR⁷—. In various embodiments of X₁, j is 1, and W¹ is—NH—. In various embodiments of X₁, j is 1, and W¹ is —S(O)₀₋₂. Invarious embodiments of X₁, j is 1, and W¹ is —C(O)—. In variousembodiments of X₁, j is 1, and W¹ is —C(O)N(R⁷). In various embodimentsof X₁, j is 1, and W¹ is —N(R⁷)C(O). In various embodiments of X₁, j is1, and W¹ is —N(R⁷)S(O). In various embodiments of X₁, j is 1, and W¹ is—N(R⁷)S(O)₂—. In various embodiments of X₁, j is 1, and W¹ is —C(O)O—.In various embodiments of X₁, j is 1, and W¹ is CH(R⁷)N(C(O)OR⁸)—. Invarious embodiments of X₁, j is 1, and W¹ is —CH(R⁷)N(C(O)R⁸)—. Invarious embodiments of X₁, j is 1, and W¹ is —CH(R⁷)N(SO₂R)—. In variousembodiments of X₁, j is 1, and W¹ is —CH(R⁷)N(R⁸)—. In variousembodiments of X₁, j is 1, and W¹ is —CH(R⁷)C(O)N(R⁸)—. In variousembodiments of X₁, j is 1, and W¹ is —CH(R⁷)N(R⁸)C(O)—. In variousembodiments of X₁, j is 1, and W¹ is —CH(R⁷)N(R⁸)S(O)—. In variousembodiments of X₁, j is 1, and W¹ is —CH(R⁷)N(R⁸)S(O)₂—.

In another embodiment, X₁ is N.

In various embodiments, X₂ is N. In other embodiments, X₂ is C.

In various embodiments, E² is -(W¹)_(j)-R⁴, where j is 0.

In another embodiment, E² is CH. In yet another embodiment, E² isC-halogen, where halogen is Cl, F, Br, or I.

In various embodiments of E², it is -(W¹)_(j)-R⁴. In various embodimentsof E², j is 1, and W¹ is —O—. In various embodiments of E², j is 1, andW¹ is —NR⁷—. In various embodiments of E², j is 1, and W¹ is —NH—. Invarious embodiments of E², j is 1, and W¹ is —S(O)₀₋₂—. In variousembodiments of E², j is 1, and W¹ is —C(O)—. In various embodiments ofE², j is 1, and W¹ is —C(O)N(R⁷)—. In various embodiments of E², j is 1,and W¹ is —N(R⁷)C(O)—. In various embodiments of E², j is 1, and W¹ is—N(R⁷)S(O)—. In various embodiments of E², j is 1, and W¹ is—N(R⁷)S(O)₂—. In various embodiments of E², j is 1, and W¹ is —C(O)O—.In various embodiments of E², j is 1, and W¹ is CH(R⁷)N(C(O)OR)—. Invarious embodiments of E², j is 1, and W¹ is —CH(R⁷)N(C(O)R)—. Invarious embodiments of E², j is 1, and W¹ is —CH(R⁷)N(SO₂R)—. In variousembodiments of E², j is 1, and W¹ is —CH(R⁷)N(R⁸)—. In variousembodiments of E², j is 1, and W¹ is —CH(R⁷)C(O)N(R⁸)—. In variousembodiments of E², j is 1, and W¹ is —CH(R⁷)N(R⁸)C(O)—. In variousembodiments of E², j is 1, and W¹ is —CH(R⁷)N(R⁸)S(O)—. In variousembodiments of E², j is 1, and W¹ is —CH(R⁷)N(R⁸)S(O)₂—.

In various embodiments, k is 0. In other embodiments, k is 1 and W² is—O—. In another embodiment, k is 1 and W² is —NR⁷—. In yet anotherembodiment of, k is 1, and W² is —S(O)₀₋₂—. In another embodiment of, kis 1 and W² is —C(O)—. In a further embodiment, k is 1 and W² is—C(O)N(R⁷)—. In another embodiment, k is 1, and W² is —N(R⁷)C(O)—. Inanother embodiment, k is 1 and W² is —N(R⁷)C(O)N(R⁸)—. In yet anotherembodiment, k is 1 and W² is —N(R⁷)S(O)—. In still yet anotherembodiment, k is 1 and W² is —N(R⁷)S(O)₂—. In a further embodiment, k is1 and W² is —C(O)O—. In another embodiment, k is 1 and W² is—CH(R⁷)N(C(O)OR)—. In another embodiment, k is 1 and W² is—CH(R⁷)N(C(O)R⁸)—. In another embodiment, k is 1 and W² is—CH(R⁷)N(SO₂R⁸)—. In a further embodiment, k is 1 and W² is—CH(R⁷)N(R⁸)—. In another embodiment, k is 1 and W² is—CH(R⁷)C(O)N(R⁸)—. In yet another embodiment, k is 1 and W² is—CH(R⁷)N(R⁸)C(O)—. In another embodiment, k is 1 and W² is—CH(R⁷)N(R⁸)S(O)—. In yet another embodiment, k is 1 and W² is—CH(R⁷)N(R⁸)S(O)₂—.

The invention also provides a compound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein: X₁ is N or C-E¹,X₂ is N, and X₃ is C; or X₁ is N or C-E¹, X₂ is C₁ and X₃ is N;

R₁ is —H, -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl,-L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl, -L-aryl, -L-heteroaryl, -L-C₁₋₁₀alkylaryl,-L-C₁₋₁₀alkylhetaryl, -L-C₁₋₁₀alkylheterocylyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₂₋₁₀alkenyl-C₃₋₈cycloalkyl,-L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl, -L-heteroalkyl, -L-heteroalkylaryl,-L-heteroalkylheteroaryl, -L-heteroalkyl-heterocylyl,-L-heteroalkyl-C₃₋₈cycloalkyl, -L-aralkyl, -L-heteroaralkyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

M₁ is a moiety having the structure of Formula A-1 or Formula A-2:

k is 0 or 1;

E¹ and E² are independently -(W¹)_(j)-R⁴;

j in E¹ or j in E², is independently 0 or 1;

W¹ is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—, —CH(R⁷)N(C(O)OR)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or CH(R⁷)N(R⁸)S(O)₂—;

W² is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)C(O)N(R⁸)—, —N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—, —CH(R⁷)N(C(O)OR)—,—CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—;

R² is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,aryl (e.g. bicyclic aryl, unsubstituted aryl, or substituted monocyclicaryl), hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl,C₃₋₈cycloalkyl-C₁₋₁₀alkyl, C₃₋₈cycloalkyl-C₂₋₁₀alkenyl,C₃₋₈cycloalkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkyl-C₂₋₁₀alkenyl,C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl (e.g. C₂₋₁₀alkyl-monocyclicaryl, C₁₋₁₀alkyl-substituted monocyclic aryl, or C₁₋₁₀alkylbicycloaryl),C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl,C₂₋₁₀alkynylheteroalkyl, C₂₋₁₀alkynylheterocylyl,C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxy C₁₋₁₀alkyl,C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl,heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl (e.g. monocyclicaryl-C₂₋₁₀alkyl, substituted monocyclic aryl-C₁₋₁₀alkyl, orbicycloaryl-C₁₋₁₀alkyl), aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl,hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl, hetaryl-heteroalkyl, orhetaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroarylmoiety is unsubstituted, or wherein each of bicyclic aryl, heteroarylmoiety or monocyclic aryl moiety is substituted with one or moreindependent alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo,—OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³²,—SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³,—NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³²,—NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³²,—OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³², and whereineach of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety isunsubstituted or is substituted with one or more alkyl, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—O-aryl, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or—C(═O)NR³¹R³²;

R³ and R⁴ are independently hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³², aryl, hetaryl, C₁₋₄alkyl,C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl,C₃₋₈cycloalkyl-C₁₋₁₀alkyl, C₃₋₈cycloalkyl-C₂₋₁₀alkenyl,C₃₋₈cycloalkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkyl-C₂₋₁₀alkenyl,C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl, C₁₋₁₀alkylhetaryl,C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl,heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl,heteroalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein eachof said aryl or heteroaryl moiety is unsubstituted or is substitutedwith one or more independent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵,—NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹,C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

R⁵ is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³²;

R³¹, R³², and R³³, in each instance, are independently H or C₁₋₁₀alkyl,wherein the C₁₋₁₀alkyl is unsubstituted or is substituted with one ormore aryl, heteroalkyl, heterocyclyl, or hetaryl group wherein each ofsaid aryl, heteroalkyl, heterocyclyl, or hetaryl group is unsubstitutedor is substituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃,—O-aryl, OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl),—NH(C₁₋₁₀alkyl), —NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl),—C(O)(C₁₋₁₀alkyl-aryl), —C(O)(aryl), —CO₂—C₁₋₁₀alkyl,—CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl, —C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl),—C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵, —C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl),—O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂ aryl, —SO₂N(aryl),—SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or —SO₂NR³⁴R³⁵;

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen atom;

R⁷ and R⁸ are each independently hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,aryl, heteroaryl, heterocyclyl or C₃₋₁₀cycloalkyl, each of which exceptfor hydrogen is unsubstituted or is substituted by one or moreindependent R⁶;

R⁶ is halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl; aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, whereineach of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl,or hetaryl group is unsubstituted or is substituted with one or moreindependent halo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², or—NR³⁴R³⁵; and

R⁹ is H, halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl; aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, whereineach of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl,or hetaryl group is unsubstituted or is substituted with one or moreindependent halo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², or—NR³⁴R³⁵.

In various embodiments of the compound of Formula III, the compound hasa structure of Formula III-A or Formula III-B:

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula III-A, X₁ is N and X₂ is N. In otherembodiments, X₁ is C-E¹ and X₂ is N. In yet other embodiments, X₁ is NHand X₂ is C. In further embodiments, X₁ is CH-E¹ and X₂ is C.

In several embodiments of Formula III-B, X₁ is N and X₂ is C. In furtherembodiments, X₁ is C-E¹ and X₂ is C.

In various embodiments, X₁ is C-(W¹)_(j)-R⁴, where j is 0.

In another embodiment, X₁ is CH. In yet another embodiment, X₁ isC-halogen, where halogen is Cl, F, Br, or I.

In various embodiments of X₁, it is C-(W¹)_(j)-R⁴. In variousembodiments of X₁, j is 1, and W¹ is —O—. In various embodiments of X₁,j is 1, and W¹ is —NR⁷—. In various embodiments of X₁, j is 1, and W¹ is—NH—. In various embodiments of X₁, j is 1, and W¹ is —S(O)₀₋₂—. Invarious embodiments of X₁, j is 1, and W¹ is —C(O)—. In variousembodiments of X₁, j is 1, and W¹ is —C(O)N(R⁷)—. In various embodimentsof X₁, j is 1, and W¹ is —N(R⁷)C(O)—. In various embodiments of X₁, j is1, and W¹ is —N(R⁷)S(O)—. In various embodiments of X₁, j is 1, and W¹is —N(R⁷)S(O)₂—. In various embodiments of X₁, j is 1, and W¹ is—C(O)O—. In various embodiments of X₁, j is 1, and W¹ isCH(R⁷)N(C(O)OR)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)N(C(O)R)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)N(SO₂R)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)N(R⁸)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)C(O)N(R⁸)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)N(R⁸)C(O)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)N(R⁸)S(O)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)N(R⁸)S(O)₂—.

In various embodiments, X₁ is CH-(W¹)_(j)-R⁴, where j is 0.

In another embodiment, X₁ is CH₂. In yet another embodiment, X₁ isCH-halogen, where halogen is Cl, F, Br, or I.

In various embodiments of X₁, it is CH-(W¹)_(j)-R⁴. In variousembodiments of X₁, j is 1, and W¹ is —O—. In various embodiments of X₁,j is 1, and W¹ is —NR⁷—. In various embodiments of X₁, j is 1, and W¹ is—NH—. In various embodiments of X₁, j is 1, and W¹ is —S(O)₀₋₂—. Invarious embodiments of X₁, j is 1, and W¹ is —C(O)—. In variousembodiments of X₁, j is 1, and W¹ is —C(O)N(R⁷)—. In various embodimentsof X₁, j is 1, and W¹ is —N(R⁷)C(O)—. In various embodiments of X₁, j is1, and W¹ is —N(R⁷)S(O)—. In various embodiments of X₁, j is 1, and W¹is —N(R⁷)S(O)₂—. In various embodiments of X₁, j is 1, and W¹ is—C(O)O—. In various embodiments of X₁, j is 1, and W¹ isCH(R⁷)N(C(O)OR)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)N(C(O)R)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)N(SO₂R)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)N(R⁸)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)C(O)N(R⁸)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)N(R⁸)C(O)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)N(R⁸)S(O)—. In various embodiments of X₁, j is 1, and W¹ is—CH(R⁷)N(R⁸)S(O)₂—.

In another embodiment, X₁ is N.

In various embodiments, X₂ is N. In other embodiments, X₂ is C.

In various embodiments, E² is -(W¹)_(j)-R⁴, where j is 0.

In another embodiment, E² is CH. In yet another embodiment, E² isC-halogen, where halogen is Cl, F, Br, or I.

In various embodiments of E², it is -(W¹)_(j)-R⁴. In various embodimentsof E², j is 1, and W¹ is —O—. In various embodiments of E², j is 1, andW¹ is —NR⁷—. In various embodiments of E², j is 1, and W¹ is —NH—. Invarious embodiments of E², j is 1, and W¹ is —S(O)₀₋₂—. In variousembodiments of E², j is 1, and W¹ is —C(O)—. In various embodiments ofE², j is 1, and W¹ is —C(O)N(R⁷)—. In various embodiments of E², j is 1,and W¹ is —N(R⁷)C(O)—. In various embodiments of E², j is 1, and W¹ is—N(R⁷)S(O)—. In various embodiments of E², j is 1, and W¹ is—N(R⁷)S(O)₂—. In various embodiments of E², j is 1, and W¹ is —C(O)O—.In various embodiments of E², j is 1, and W¹ is CH(R⁷)N(C(O)OR)—. Invarious embodiments of E², j is 1, and W¹ is —CH(R⁷)N(C(O)R)—. Invarious embodiments of E², j is 1, and W¹ is —CH(R⁷)N(SO₂R)—. In variousembodiments of E², j is 1, and W¹ is —CH(R⁷)N(R⁸)—. In variousembodiments of E², j is 1, and W¹ is —CH(R⁷)C(O)N(R⁸)—. In variousembodiments of E², j is 1, and W¹ is —CH(R⁷)N(R⁸)C(O)—. In variousembodiments of E², j is 1, and W¹ is —CH(R⁷)N(R⁸)S(O)—. In variousembodiments of E², j is 1, and W¹ is —CH(R⁷)N(R⁸)S(O)₂—.

In various embodiments when M₁ is a moiety of Formula A-1, M₁ isbenzoxazolyl substituted with -(W₂)_(k)-R₂. In some embodiments, M₁ is abenzoxazolyl moiety, substituted at the 2-position with -(W₂)_(k)-R₂. Insome embodiments, M₁ is either a 5-benzoxazolyl or a 6-benzoxazolylmoiety, optionally substituted with -(W₂)_(k)-R₂. Exemplary Formula A-1M₁ moieties include but are not limited to the following:

In various embodiments when M₁ is a moiety of Formula A-2, Formula A-2is an aza-substituted benzoxazolyl moiety having a structure of one ofthe following formulae:

Exemplary Formula A-2 M₁ moieties include but are not limited to thefollowing:

In various embodiments of M₁, k is 0. In other embodiments of M₁, k is 1and W² is —O—. In another embodiment of M₁, k is 1 and W² is —NR⁷—. Inyet another embodiment of M₁, k is 1 and W² is —S(O)₀₋₂—. In anotherembodiment of M₁, k is 1 and W² is —C(O)—. In a further embodiment ofM₁, k is 1 and W² is —C(O)N(R⁷)—. In another embodiment of M₁, k is 1and W² is —N(R⁷)C(O)—. In another embodiment, k is 1 and W² is—N(R⁷)C(O)N(R⁸)—. In yet another embodiment of M₁, k is 1 and W² is—N(R⁷)S(O)—. In still yet another embodiment of M₁, k is 1 and W² is—N(R⁷)S(O)₂—. In a further embodiment of M₁, k is 1 and W² is —C(O)O—.In another embodiment of M₁, k is 1 and W² is —CH(R⁷)N(C(O)OR⁸)—. Inanother embodiment of M₁, k is 1 and W² is —CH(R⁷)N(C(O)R⁸)—. In anotherembodiment of M₁, k is 1 and W² is —CH(R⁷)N(SO₂R⁸)—. In a furtherembodiment of M₁, k is 1 and W² is —CH(R⁷)N(R⁸)—. In another embodimentof M₁, k is 1 and W² is —CH(R⁷)C(O)N(R⁸)—. In yet another embodiment ofM₁, k is 1 and W² is —CH(R⁷)N(R⁸)C(O)—. In another embodiment of M₁, kis 1 and W² is —CH(R⁷)N(R⁸)S(O)—. In yet another embodiment of M₁, k is1 and W² is —CH(R⁷)N(R⁸)S(O)₂—.

In some aspects of the invention, a compound of Formula I′-A′ is acompound of Formula IV-A or Formula IV-B:

or a pharmaceutically acceptable salt thereof.

In various embodiments of the compound of Formula IV-A, the compound hasa structure of Formula IV-A-1 or Formula IV-A-2:

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula IV-A-1, X₁ is N and X₂ is N. In otherembodiments, X₁ is C-E¹ and X₂ is N. In yet other embodiments, X₁ is NHand X₂ is C. In further embodiments, X₁ is CH-E¹ and X₂ is C. In severalembodiments of Formula IV-A-2, X₁ is N and X₂ is C. In furtherembodiments, X₁ is C-E¹ and X₂ is C.

In some embodiments, X₄ is CR⁹. In other embodiments, X₄ is N.

In various embodiments of the compound of Formula II-B, the compound hasa structure of Formula II-B-1 or Formula II-B-2:

or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula IV-B-1, X₁ is N and X₂ is N. In otherembodiments, X₁ is C-E¹ and X₂ is N. In yet other embodiments, X₁ is NHand X₂ is C. In further embodiments, X₁ is CH-E¹ and X₂ is C.

In several embodiments of Formula IV-B-2, X₁ is N and X₂ is C. Infurther embodiments, X₁ is C-E¹ and X₂ is C.

In some embodiments, X₄ is CR⁹. In other embodiments, X₄ is N.

Additional embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, B (includingB′ and B″), C, 3-1, 3-3, 3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″,3-6″, N-1, N-3, N-1″, or N-3″ are described below.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, C, 3-1, 3-3,3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, A, A″, C, 3-1, 3-3, 3-4, 3-5,3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, or N-3″, L isabsent. In another embodiment, L is —(C═O)—. In another embodiment, L is—C(═O)O—. In a further embodiment, L is —C(═O)NR³¹—. In yet anotherembodiment, L is —S—. In one embodiment, L is —S(O)—. In anotherembodiment, L is —S(O)₂—. In yet another embodiment, L is —S(O)₂NR³¹—.In another embodiment, L is —NR³¹—.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, C, 3-1, 3-3,3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, R₁ is -L-C₁₋₁₀alkyl, which is unsubstituted. In anotherembodiment, R₁ is -L-C₁₋₁₀alkyl, which is substituted by one or moreindependent R³. In yet another embodiment, R₁ is -L- unsubstitutedC₁₋₁₀alkyl, where L is absent. In another embodiment, R₁ is-L-C₁₋₁₀alkyl, which is substituted by one or more independent R³, and Lis absent.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, C, 3-1, 3-3,3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, R₁ is -L-C₃₋₈cycloalkyl, which is unsubstituted. In anotherembodiment, R₁ is -L-C₃₋₈cycloalkyl, which is substituted by one or moreindependent R³. In yet another embodiment, R₁ is -L-C₃₋₈cycloalkyl,which is unsubstituted, and L is absent. In a further embodiment, R₁ is-L-C₃₋₈cycloalkyl which is substituted by one or more independent R³,and L is absent.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, C, 3-1, 3-3,3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, R₁ is H.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (IV-B-1 and IV-B-2), A, C, 3-1, 3-3, 3-4, 3-5,3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, or N-3″, R₁ is-L-aryl, which is unsubstituted. In another embodiment, R₁ is -L-aryl,which is substituted by one or more independent R³. In anotherembodiment, R₁ is -L-aryl which is unsubstituted, and L is absent. Inyet another embodiment, R₁ is -L-aryl, which is substituted by one ormore independent R³, and L is absent.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, C, 3-1, 3-3,3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, R₁ is -L-heteroaryl, which is unsubstituted. In anotherembodiment, R₁ is -L-heteroaryl, which is substituted by one or moreindependent R³. In a further embodiment, R₁ is -L-heteroaryl which isunsubstituted and L is absent. In yet another embodiment, R₁ is-L-heteroaryl, which is substituted by one or more independent R³, and Lis absent.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, C, 3-1, 3-3,3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, R₁ is -L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl, which is unsubstituted. Inanother embodiment, R₁ is -L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl, which issubstituted by one or more independent R³. In a further embodiment, R₁is -L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl which is unsubstituted and L is absent.In yet another embodiment, R₁ is -L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl, which issubstituted by one or more independent R³, and L is absent.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, C, 3-1, 3-3,3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, R₁ is -L-C₁₋₁₀alkylaryl, which is unsubstituted. In anotherembodiment, R₁ is -L-C₁₋₁₀alkylaryl, which is substituted by one or moreindependent R³. In a further embodiment, R₁ is -L-C₁₋₁₀alkylaryl whichis unsubstituted and L is absent. In yet another embodiment, R₁ is-L-C₁₋₁₀alkylaryl, which is substituted by one or more independent R³,where L is absent.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, C, 3-1, 3-3,3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, R₁ is -L-C₁₋₁₀alkylhetaryl, which is unsubstituted. In anotherembodiment, R₁ is -L-C₁₋₁₀alkylhetaryl, which is substituted by one ormore independent R³. In a further embodiment, R₁ is -L-C₁₋₁₀alkylhetarylwhich is unsubstituted and L is absent. In yet another embodiment, R₁ is-L-C₁₋₁₀alkylhetaryl, which is substituted by one or more independentR³, where L is absent.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, C, 3-1, 3-3,3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, R₁ is -L-C₁₋₁₀alkylheterocylyl, which is unsubstituted. In anotherembodiment, R₁ is -L-C₁₋₁₀alkylheterocylyl, which is substituted by oneor more independent R³. In a further embodiment, R₁ is-L-C₁₋₁₀alkylheterocylyl which is unsubstituted and L is absent. In yetanother embodiment, R₁ is -L-C₁₋₁₀alkylheterocylyl, which is substitutedby one or more independent R³, where L is absent.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, C, 3-1, 3-3,3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, R₁ is -L-C₂₋₁₀alkenyl, which is unsubstituted. In anotherembodiment, R₁ is -L-C₂₋₁₀alkenyl which is substituted by one or moreindependent R³. In a further embodiment, R₁ is -L-C₂₋₁₀alkenyl which isunsubstituted and L is absent. In yet another embodiment, R₁ is-L-C₂₋₁₀alkenyl, which is substituted by one or more independent R³,where L is absent.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, C, 3-1, 3-3,3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, R₁ is -L-C₂₋₁₀alkynyl, which is unsubstituted. In anotherembodiment, R₁ is -L-C₂₋₁₀alkynyl which is substituted by one or moreindependent R³. In a further embodiment, R₁ is -L-C₂₋₁₀alkynyl which isunsubstituted and L is absent. In yet another embodiment, R₁ is-L-C₂₋₁₀alkynyl, which is substituted by one or more independent R³,where L is absent.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, C, 3-1, 3-3,3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, R₁ is -L-C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, which is unsubstituted. Inanother embodiment, R₁ is -L-C₂₋₁₀alkenyl-C₃₋₈cycloalkyl which issubstituted by one or more independent R³. In a further embodiment, R₁is -L-C₂₋₁₀alkenyl-C₃₋₈cycloalkyl which is unsubstituted and L isabsent. In yet another embodiment, R₁ is -L-C₂₋₁₀alkenyl-C₃₋₈cycloalkyl,which is substituted by one or more independent R³, where L is absent.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, C, 3-1, 3-3,3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, R₁ is -L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl, which is unsubstituted. Inanother embodiment, R₁ is -L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl which issubstituted by one or more independent R³. In a further embodiment, R₁is -L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl which is unsubstituted and L isabsent. In yet another embodiment, R₁ is -L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,which is substituted by one or more independent R³, where L is absent.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, A″, C, 3-1,3-3, 3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, R₁ is -L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl, which is unsubstituted. Inanother embodiment, R₁ is -L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl which issubstituted by one or more independent R³. In a further embodiment, R₁is -L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl which is unsubstituted and L isabsent. In yet another embodiment, R₁ is -L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,which is substituted by one or more independent R³, where L is absent.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, A″, C, 3-1,3-3, 3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, R₁ is -L-heteroalkyl, which is unsubstituted. In anotherembodiment, R₁ is -L-heteroalkyl which is substituted by one or moreindependent R³. In a further embodiment, R₁ is -L-heteroalkyl which isunsubstituted and L is absent. In yet another embodiment, R₁ is-L-heteroalkyl, which is substituted by one or more independent R³,where L is absent.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, A″, C, 3-1,3-3, 3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, R₁ is -L-heteroalkylaryl, which is unsubstituted. In anotherembodiment, R₁ is -L-heteroalkylaryl which is substituted by one or moreindependent R³. In a further embodiment, R₁ is -L-heteroalkylaryl whichis unsubstituted and L is absent. In yet another embodiment, R₁ is-L-heteroalkylaryl, which is substituted by one or more independent R³,where L is absent.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, A″, C, 3-1,3-3, 3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, R₁ is -L-heteroalkylheteroaryl, which is unsubstituted. In anotherembodiment, R₁ is -L-heteroalkylheteroaryl, which is substituted by oneor more independent R³. In a further embodiment, R₁ is-L-heteroalkylheteroaryl which is unsubstituted and L is absent. In yetanother embodiment, R₁ is -L-heteroalkylheteroaryl, which is substitutedby one or more independent R³, where L is absent.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, A″, C, 3-1,3-3, 3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, R₁ is -L-heteroalkyl-heterocylyl, which is unsubstituted. Inanother embodiment, R₁ is -L-heteroalkyl-heterocylyl, which issubstituted by one or more independent R³. In a further embodiment, R₁is -L-heteroalkyl-heterocylyl which is unsubstituted, and L is absent.In yet another embodiment, R₁ is -L-heteroalkyl-heterocylyl, which issubstituted by one or more independent R³, where L is absent.

In In various embodiments of compounds of Formula I′-A′, I (includingI-A and I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B(including II-B-1 and II-B-2), III (including III-A and III-B), IV-A(including IV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A,A″, C, 3-1, 3-3, 3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1,N-3, N-1″, or N-3″, R₁ is -L-heteroalkyl-C₃₋₈cycloalkyl, which isunsubstituted. In another embodiment, R₁ is-L-heteroalkyl-C₃₋₈cycloalkyl, which is substituted by one or moreindependent R³. In a further embodiment, R₁ is-L-heteroalkyl-C₃₋₈cycloalkyl which is unsubstituted and L is absent. Inyet another embodiment, R₁ is -L-heteroalkyl-C₃₋₈cycloalkyl, which issubstituted by one or more independent R³, where L is absent.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, A″, C, 3-1,3-3, 3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, R₁ is -L-aralkyl, which is unsubstituted. In another embodiment,R₁ is -L-aralkyl, which is substituted by one or more independent R³. Ina further embodiment, R₁ is -L-aralkyl which is unsubstituted. In yetanother embodiment, R₁ is -L-aralkyl, which is substituted by one ormore independent R³, where L is absent.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, A″, C, 3-1,3-3, 3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, R₁ is -L-heteroaralkyl, which is unsubstituted. In anotherembodiment, R₁ is -L-heteroaralkyl, which is substituted by one or moreindependent R³. In a further embodiment, R₁ is -L-heteroaralkyl which isunsubstituted and L is absent. In yet another embodiment, R₁ is-L-heteroaralkyl, which is substituted by one or more independent R³,where L is absent.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1 and II-A-2), II-B (including II-B-1 andII-B-2), III (including III-A and III-B), IV-A (including IV-A-1 andIV-A-2), IV-B (including IV-B-1 and IV-B-2), A, C, 3-1, 3-3, 3-4, 3-5,3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, or N-3″, R₁ is-L-heterocyclyl, which is unsubstituted. In another embodiment, R₁ is-L-heterocyclyl, which is substituted by one or more independent R³. Ina further embodiment, R₁ is -L-heterocyclyl which is unsubstituted and Lis absent. In yet another embodiment, R₁ is -L-heterocyclyl, which issubstituted by one or more independent R³, where L is absent.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, A″, C, 3-1,3-3, 3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, R₁ is a substituent as shown below:

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), B (including B′and B″), C, 3-6, C″, or 3-6″, R² is hydrogen. In another embodiment, R²is halogen. In another embodiment, R² is OH. In another embodiment, R²is R³¹. In another embodiment, R² is CF₃. In another embodiment, R² isOCF₃. In another embodiment, R² is OR³¹. In another embodiment, R² isNR³¹R³². In another embodiment, R² is NR³⁴R³⁵. In another embodiment, R²is —C(O)R³¹. In another embodiment, R² is —CO₂R³¹. In anotherembodiment, R² is —C(═O)NR³¹R³². In another embodiment, R² isC(═O)NR³⁴R³⁵. In another embodiment, R² is —NO₂. In another embodiment,R² is —CN. In another embodiment, R² is —S(O)₀₋₂R³. In anotherembodiment, R² is SO₂NR³¹R³². In another embodiment, R² is —SO₂NR³⁴R³⁵.In another embodiment, R² is —NR³¹C(═O)R³². In another embodiment, R² isNR³¹C(═O)OR³². In another embodiment, R² is NR³¹C(═O)NR³²R³³. In anotherembodiment, R² is NR³¹S(O)₀₋₂R³². In another embodiment, R² is—C(═S)OR³¹. In another embodiment, R² is —C(═O)SR³¹. In anotherembodiment, R² is NR³¹C(═NR³²)NR³³R³². In another embodiment, R² isNR³¹C(═NR³²)OR³³. In another embodiment, R² is —NR³¹C(═NR³²)SR³³. Inanother embodiment, R² is —OC(═O)OR³³. In another embodiment, R² is—OC(═O)NR³¹R³². In another embodiment, R² is —OC(═O)SR³¹. In anotherembodiment, R² is —SC(═O)OR³¹. In another embodiment, R² is—P(O)OR³¹OR³². In another embodiment, R² is —SC(═O)NR³¹R³². In anotherembodiment, R² is monocyclic aryl. In another embodiment, R² is bicyclicaryl. In another embodiment, R² is substituted monocyclic aryl. Inanother embodiment, R² is hetaryl. In another embodiment, R² isC₁₋₄alkyl. In another embodiment, R² is C₁₋₁₀alkyl. In anotherembodiment, R² is C₃₋₈cycloalkyl. In another embodiment, R² isC₃₋₈cycloalkyl-C₁₋₁₀alkyl. In another embodiment, R² isC₁₋₁₀alkyl-C₃₋₈cycloalkyl. In another embodiment, R² isC₁₋₁₀alkyl-monocyclic aryl. In another embodiment, R² isC₂₋₁₀alkyl-monocyclic aryl. In another embodiment, R² is monocyclicaryl-C₂₋₁₀alkyl. In another embodiment, R² is C₁₋₁₀alkyl-bicyclicaryl.In another embodiment, R² is bicyclicaryl-C₁₋₁₀alkyl. In anotherembodiment, R² is —C₁₋₁₀alkylhetaryl. In another embodiment, R² isC₁₋₁₀alkylheterocyclyl. In another embodiment, R² is C₂₋₁₀alkenyl. Inanother embodiment, R² is C₂₋₁₀alkynyl. In another embodiment, R² isC₂₋₁₀alkenylaryl. In another embodiment, R² is C₂₋₁₀alkenylhetaryl. Inanother embodiment, R² is C₂₋₁₀alkenylheteroalkyl. In anotherembodiment, R² is C₂₋₁₀alkenylheterocyclcyl. In another embodiment, R²is —C₂₋₁₀alkynylaryl. In another embodiment, R² is C₂₋₁₀alkynylhetaryl.In another embodiment, R² is C₂₋₁₀alkynylheteroalkyl. In anotherembodiment, R² is —C₂₋₁₀alkynylheterocylyl. In another embodiment, R² is—C₂₋₁₀alkynylC₃₋₈cycloalkyl. In another embodiment, R² isC₂₋₁₀alkynylC₃₋₈cycloalkenyl. In another embodiment, R² is—C₁₋₁₀alkoxy-C₁₋₁₀alkyl. In another embodiment, R² isC₁₋₁₀alkoxy-C₂₋₁₀alkenyl. In another embodiment, R² isC₁₋₁₀alkoxy-C₂₋₁₀alkynyl. In another embodiment, R² is -heterocyclylC₁₋₁₀alkyl. In another embodiment, R² is heterocyclylC₂₋₁₀alkenyl. Inanother embodiment, R² is heterocyclylC₂₋₁₀alkynyl. In anotherembodiment, R² is aryl-C₂₋₁₀alkyl. In another embodiment, R² isaryl-C₁₋₁₀alkyl. In another embodiment, R² is aryl-C₂₋₁₀alkenyl. Inanother embodiment, R² is aryl-C₂₋₁₀alkynyl. In another embodiment, R²is aryl-heterocyclyl. In another embodiment, R² is hetaryl-C₁₋₁₀alkyl.In another embodiment, R² is hetaryl-C₂₋₁₀alkenyl. In anotherembodiment, R² is hetaryl-C₂₋₁₀alkynyl. In another embodiment, R² ishetaryl-C₃₋₈cycloalkyl. In another embodiment, R² ishetaryl-heteroalkyl. In another embodiment, R² is hetaryl-heterocyclyl.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), C, 3-6, C″, or3-6″, when R² is bicyclic aryl, monocyclic aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,monocyclic aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is unsubstituted. In various embodiments,when R² is bicyclic aryl, monocyclic aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,monocyclic aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent halo. In another embodiment, when R² is bicyclic aryl,monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl,heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl,heterocyclyl C₁₋₁₀alkyl, or C₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substitutedwith one or more independent —OH. In another embodiment, when R² isbicyclic aryl, monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl,heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, monocyclicaryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, or C₃₋₈cycloalkyl-C₁₋₁₀alkyl,it is substituted with one or more independent —R³¹. In anotherembodiment, when R² is bicyclic aryl, monocyclic aryl, hetaryl,C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —CF₃. In another embodiment, when R² is bicyclic aryl,monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl,heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl,heterocyclyl C₁₋₁₀alkyl, or C₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substitutedwith one or more independent —OCF. In another embodiment, when R² isbicyclic aryl, monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl,heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, monocyclicaryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, or C₃₋₈cycloalkyl-C₁₋₁₀alkyl,it is substituted with one or more independent —OR³¹. In anotherembodiment, when R² is bicyclic aryl, monocyclic aryl, hetaryl,C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —NR³¹R³². In another embodiment, when R² is bicyclic aryl,monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl,heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl,heterocyclyl C₁₋₁₀alkyl, or C₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substitutedwith one or more independent —NR³⁴R³⁵. In another embodiment, when R⁴ isbicyclic aryl, monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl,heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, monocyclicaryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, or C₃₋₈cycloalkyl-C₁₋₁₀alkyl,it is substituted with one or more independent —C(O)R³¹. In anotherembodiment, when R² is bicyclic aryl, monocyclic aryl, hetaryl,C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —CO₂R³¹. In another embodiment, when R² is bicyclic aryl,monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl,heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl,heterocyclyl C₁₋₁₀alkyl, or C₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substitutedwith one or more independent —C(═O)NR³¹R³². In another embodiment, whenR² is bicyclic aryl, monocyclic aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,monocyclic aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —C(═O)NR³⁴R³⁵. In another embodiment, when R² is bicyclicaryl, monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl,heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, monocyclicaryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, or C₃₋₈cycloalkyl-C₁₋₁₀alkyl,it is substituted with one or more independent —NO₂. In anotherembodiment, when R² is bicyclic aryl, monocyclic aryl, hetaryl,C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —CN. In another embodiment, when R² is bicyclic aryl,monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl,heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl,heterocyclyl C₁₋₁₀alkyl, or C₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substitutedwith one or more independent —S(O)₀₋₂R³¹. In another embodiment, when R²is bicyclic aryl, monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl,heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, monocyclicaryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, or C₃₋₈cycloalkyl-C₁₋₁₀alkyl,it is substituted with one or more independent —SO₂NR³¹R³². In anotherembodiment, when R² is bicyclic aryl, monocyclic aryl, hetaryl,C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —SO₂NR³⁴R³⁵. In another embodiment, when R² is bicyclicaryl, monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl,heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, monocyclicaryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, or C₃₋₈cycloalkyl-C₁₋₁₀alkyl,it is substituted with one or more independent NR³¹C(═O)R³². In anotherembodiment, when R² is bicyclic aryl, monocyclic aryl, hetaryl,C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —NR³¹C(═O)OR³². In another embodiment, when R² is bicyclicaryl, monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl,heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, monocyclicaryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, or C₃₋₈cycloalkyl-C₁₋₁₀alkyl,it is substituted with one or more independent —NR³¹C(═O)NR³²R³³. Inanother embodiment, when R² is bicyclic aryl, monocyclic aryl, hetaryl,C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —NR³¹S(O)₀₋₂R³². In another embodiment, when R² is bicyclicaryl, monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl,heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, monocyclicaryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, or C₃₋₈cycloalkyl-C₁₋₁₀alkyl,it is substituted with one or more independent —C(═S)OR³¹. In anotherembodiment, when R² is bicyclic aryl, monocyclic aryl, hetaryl,C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —C(═O)SR³¹. In another embodiment, when R² is bicyclic aryl,monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl,heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl,heterocyclyl C₁₋₁₀alkyl, or C₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substitutedwith one or more independent —NR³¹C(═NR³²)NR³³R³². In anotherembodiment, when R² is bicyclic aryl, monocyclic aryl, hetaryl,C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent, —NR³¹C(═NR³²)OR³³. In another embodiment, when R² isbicyclic aryl, monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl,heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, monocyclicaryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, or C₃₋₈cycloalkyl-C₁₋₁₀alkyl,it is substituted with one or more independent —NR³¹C(═NR³²)SR³³. Inanother embodiment, when R² is bicyclic aryl, monocyclic aryl, hetaryl,C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —OC(═O)OR³³. In another embodiment, when R² is bicyclicaryl, monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl,heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, monocyclicaryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, or C₃₋₈cycloalkyl-C₁₋₁₀alkyl,it is substituted with one or more independent —OC(═O)NR³¹R³². Inanother embodiment, when R² is bicyclic aryl, monocyclic aryl, hetaryl,C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —OC(═O)SR³¹. In another embodiment, when R² is bicyclicaryl, monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl,heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, monocyclicaryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, or C₃₋₈cycloalkyl-C₁₋₁₀alkyl,it is substituted with one or more independent —SC(═O)OR³¹. In anotherembodiment, when R² is bicyclic aryl, monocyclic aryl, hetaryl,C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —P(O)OR³¹OR³². In another embodiment, when R² is bicyclicaryl, monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl,heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, monocyclicaryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, or C₃₋₈cycloalkyl-C₁₋₁₀alkyl,it is substituted with one or more independent —SC(═O)NR³¹R³². Inanother embodiment, when R² is bicyclic aryl, monocyclic aryl, hetaryl,C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent alkyl. In another embodiment, when R² is bicyclic aryl,monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl,heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl,heterocyclyl C₁₋₁₀alkyl, or C₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substitutedwith one or more independent heteroalkyl. In another embodiment, when R²is bicyclic aryl, monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl,heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, monocyclicaryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, or C₃₋₈cycloalkyl-C₁₋₁₀alkyl,it is substituted with one or more independent alkenyl. In anotherembodiment, when R² is bicyclic aryl, monocyclic aryl, hetaryl,C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent alkynyl. In another embodiment, when R² is bicyclic aryl,monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl,heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl,heterocyclyl C₁₋₁₀alkyl, or C₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substitutedwith one or more independent cycloalkyl. In another embodiment, when R²is bicyclic aryl, monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl,heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, monocyclicaryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, or C₃₋₈cycloalkyl-C₁₋₁₀alkyl,it is substituted with one or more independent heterocycloalkyl. Inanother embodiment, when R² is bicyclic aryl, monocyclic aryl, hetaryl,C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent aryl. In another embodiment, when R² is bicyclic aryl,monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl,heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl,heterocyclyl C₁₋₁₀alkyl, or C₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substitutedwith one or more independent arylalkyl. In another embodiment, when R²is bicyclic aryl, monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl,heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, monocyclicaryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, or C₃₋₈cycloalkyl-C₁₋₁₀alkyl,it is substituted with one or more independent heteroaryl. In anotherembodiment, when R² is bicyclic aryl, monocyclic aryl, hetaryl,C₁₋₁₀alkyl, C₃₋₈cycloalkyl, heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, monocyclic aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent heteroarylalkyl.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, A″, C, 3-1,3-3, 3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, R³ is hydrogen. In another embodiment, R³ is halogen. In anotherembodiment, R³ is —OH. In another embodiment, R³ is —R³¹. In anotherembodiment, R³ is —CF₃. In another embodiment, R³ is —OCF₃. In anotherembodiment, R³ is —OR³¹. In another embodiment, R³ is NR³¹R³². Inanother embodiment, R³ is —NR³⁴R³⁵. In another embodiment, R³ is—C(O)R³¹. In another embodiment, R³ is —CO₂R³¹. In another embodiment,R³ is —C(═O)NR³¹R³². In another embodiment, R³ is —C(═O)NR³⁴R³⁵. Inanother embodiment, R³ is —NO₂. In another embodiment, R³ is —CN. Inanother embodiment, R³ is S(O)₀₋₂R³. In another embodiment, R³ is—SO₂NR³¹R³². In another embodiment, R³ is —SO₂NR³⁴R³⁵. In anotherembodiment, R³ is —NR³¹C(═O)R³². In another embodiment, R³ is—NR³¹C(═O)OR³². In another embodiment, R³ is —NR³¹C(═O)NR³²R³³. Inanother embodiment, R³ is NR³¹S(O)₀₋₂R³². In another embodiment, R³ is—C(═S)OR³¹. In another embodiment, R³ is —C(═O)SR³¹. In anotherembodiment, R³ is —NR³¹C(═NR³²)NR³³R³². In another embodiment, R³ is—NR³¹C(═NR³²)OR³³. In another embodiment, R³ is —NR³¹C(═NR³²)SR³³. Inanother embodiment, R³ is —OC(═O)OR³³. In another embodiment, R³ is—OC(═O)NR³¹R³². In another embodiment, R³ is —OC(═O)SR³¹. In anotherembodiment, R³ is —SC(═O)OR³¹. In another embodiment, R³ is—P(O)OR³¹OR³². In another embodiment, R³ is —SC(═O)NR³¹R³². In anotherembodiment, R³ is aryl. In another embodiment, R² is hetaryl. In anotherembodiment, R³ is C₁₋₄alkyl. In another embodiment, R³ is C₁₋₁₀alkyl. Inanother embodiment, R³ is C₃₋₈cycloalkyl. In another embodiment, R³ isC₃₋₈cycloalkyl-C₁₋₁₀alkyl. In another embodiment, R³ is—C₁₋₁₀alkyl-C₃₋₈cycloalkyl. In another embodiment, R³ isC₂₋₁₀alkyl-monocyclic aryl. In another embodiment, R³ is monocyclicaryl-C₂₋₁₀alkyl. In another embodiment, R³ is C₁₋₁₀alkyl-bicyclicaryl.In another embodiment, R³ is bicyclicaryl-C₁₋₁₀alkyl. In anotherembodiment, R³ is C₁₋₁₀alkylhetaryl. In another embodiment, R³ isC₁₋₁₀alkylheterocyclyl. In another embodiment, R³ is C₂₋₁₀alkenyl. Inanother embodiment, R³ is C₂₋₁₀alkynyl. In another embodiment, R³ isC₂₋₁₀alkenylaryl. In another embodiment, R³ is C₂₋₁₀alkenylhetaryl. Inanother embodiment, R³ is C₂₋₁₀alkenylheteroalkyl. In anotherembodiment, R³ is C₂₋₁₀alkenylheterocyclcyl. In another embodiment, R³is —C₂₋₁₀alkynylaryl. In another embodiment, R³ is —C₂₋₁₀alkynylhetaryl.In another embodiment, R³ is —C₂₋₁₀alkynylheteroalkyl. In anotherembodiment, R³ is C₂₋₁₀alkynylheterocylyl. In another embodiment, R³ is—C₂₋₁₀alkynylC₃₋₈cycloalkyl. In another embodiment, R³ isC₂₋₁₀alkynylC₃₋₈cycloalkenyl. In another embodiment, R³ is—C₁₋₁₀alkoxy-C₁₋₁₀alkyl. In another embodiment, R³ isC₁₋₁₀alkoxy-C₂₋₁₀alkenyl. In another embodiment, R³ is—C₁₋₁₀alkoxy-C₂₋₁₀alkynyl. In another embodiment, R³ isheterocyclyl-C₁₋₁₀alkyl. In another embodiment, R³ is-heterocyclylC₂₋₁₀alkenyl. In another embodiment, R³ isheterocyclyl-C₂₋₁₀alkynyl. In another embodiment, R³ is aryl-C₁₋₁₀alkyl.In another embodiment, R³ is aryl-C₂₋₁₀alkenyl. In another embodiment,R³ is aryl-C₂₋₁₀alkynyl. In another embodiment, R³ is aryl-heterocyclyl.In another embodiment, R³ is hetaryl-C₁₋₁₀alkyl. In another embodiment,R³ is hetaryl-C₂₋₁₀alkenyl. In another embodiment, R³ ishetaryl-C₂₋₁₀alkynyl. In another embodiment, R³ ishetaryl-C₃₋₈cycloalkyl. In another embodiment, R³ ishetaryl-heteroalkyl. In another embodiment, R³ is hetaryl-heterocyclyl.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, A″, C, 3-1,3-3, 3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, when R³ is aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkyl-C₁₋₁₀alkyl, heterocyclyl, heterocyclyl C₁₋₁₀alkyl, orheteroalkyl, it is unsubstituted. In another embodiment, when R³ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent halo. In another embodiment, when R³ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —OH. In another embodiment, when R³ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —R³¹. In another embodiment, when R³ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —CF₃. In another embodiment, when R³ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —OCF. In another embodiment, when R³ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —OR³¹. In another embodiment, when R³ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent NR³¹R³². In another embodiment, when R³ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —NR³⁴R³⁵. In another embodiment, when R³ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —C(O)R³¹. In another embodiment, when R³ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —CO₂R³¹. In another embodiment, when R³ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —C(═O)NR³¹R³². In another embodiment, whenR³ is aryl, hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —C(═O)NR³⁴R³⁵. In another embodiment, when R³ is aryl,hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —NO₂. In another embodiment, when R³ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —CN. In another embodiment, when R³ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —S(O)₀₋₂R³¹. In another embodiment, when R³is aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —SO₂NR³¹R³². In another embodiment, when R³is aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —SO₂NR³⁴R³⁵. In another embodiment, when R³is aryl, hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent NR³¹C(═O)R³². In another embodiment, when R³ is aryl,hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —NR³¹C(═O)OR³². In another embodiment, when R³ is aryl,hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —NR³¹C(═O)NR³²R³³. In another embodiment, when R³ is aryl,hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —NR³¹S(O)₀₋₂R³². In another embodiment, when R³ is aryl,hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —C(═S)OR³¹. In another embodiment, when R³ is aryl, hetaryl,C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —C(═O)SR³¹. In another embodiment, when R³ is aryl, hetaryl,C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl, heterocyclyl,heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substituted with one ormore independent —NR³¹C(═NR³²)NR³³R³². In another embodiment, when R³ isaryl, hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent, —NR³¹C(═NR³²)OR³³. In another embodiment, when R³ is aryl,hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —NR³¹C(═NR³²)SR³³. In another embodiment, when R³ is aryl,hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —OC(═O)OR³³. In another embodiment, when R³ is aryl,hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent-OC(═O)NR³¹R. In another embodiment, when R³ is aryl,hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —OC(═O)SR³¹. In another embodiment, when R³ is aryl,hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —SC(═O)OR³¹. In another embodiment, when R³ is aryl,hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —P(O)OR³¹OR³². In another embodiment, whenR³ is aryl, hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —SC(═O)NR³¹R³².

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, A″, C, 3-1,3-3, 3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, R⁴ is hydrogen. In another embodiment, R⁴ is halogen. In anotherembodiment, R⁴ is —OH. In another embodiment, R⁴ is —R³¹. In anotherembodiment, R⁴ is CF₃. In another embodiment, R⁴ is OCF₃. In anotherembodiment, R⁴ is OR³¹. In another embodiment, R⁴ is NR³¹R³². In anotherembodiment, R⁴ is NR³⁴R³⁵. In another embodiment, R⁴ is —C(O)R³¹. Inanother embodiment, R⁴ is —CO₂R³¹. In another embodiment, R⁴ is—C(═O)NR³¹R³². In another embodiment, R⁴ is —C(═O)NR³⁴R³⁵. In anotherembodiment, R⁴ is —NO₂. In another embodiment, R⁴ is —CN. In anotherembodiment, R⁴ is —S(O)₀₋₂R³. In another embodiment, R⁴ is —SO₂NR³¹R³².In another embodiment, R⁴ is —SO₂NR³⁴R³⁵. In another embodiment, R⁴ is—NR³¹C(═O)R³². In another embodiment, R⁴ is —NR³¹C(═O)OR³². In anotherembodiment, R⁴ is —NR³¹C(═O)NR³²R³³. In another embodiment, R⁴ isNR³¹S(O)₀₋₂R³². In another embodiment, R⁴ is —C(═S)OR³¹. In anotherembodiment, R⁴ is —C(═O)SR³¹. In another embodiment, R⁴ is—NR³¹C(═NR³²)NR³³R³². In another embodiment, R⁴ is —NR³¹C(═NR³²)OR³³. Inanother embodiment, R⁴ is —NR³¹C(═NR³²)SR³³. In another embodiment, R⁴is —OC(═O)OR³³. In another embodiment, R⁴ is —OC(═O)NR³¹R³². In anotherembodiment, R⁴ is —OC(═O)SR³¹. In another embodiment, R⁴ is —SC(═O)OR³¹.In another embodiment, R⁴ is —P(O)OR³¹OR³². In another embodiment, R⁴ is—SC(═O)NR³¹R³². In another embodiment, R⁴ is aryl. In anotherembodiment, R⁴ is hetaryl. In another embodiment, R⁴ is C₁₋₄alkyl. Inanother embodiment, R⁴ is C₁₋₁₀alkyl. In another embodiment, R⁴ isC₃₋₈cycloalkyl. In another embodiment, R⁴ is C₁₋₁₀alkyl-C₃₋₈cycloalkyl.In another embodiment, R⁴ is C₁₋₁₀alkylaryl. In another embodiment, R⁴is C₁₋₁₀alkylhetaryl. In another embodiment, R⁴ isC₁₋₁₀alkylheterocyclyl. In another embodiment, R⁴ is C₂₋₁₀alkenyl. Inanother embodiment, R⁴ is C₂₋₁₀alkynyl. In another embodiment, R⁴ isC₂₋₁₀alkynyl-C₃₋₈cycloalkyl. R⁴ is C₂₋₁₀alkenyl-C₃₋₈cycloalkyl. Inanother embodiment, R⁴ is C₂₋₁₀alkenylaryl. In another embodiment, R⁴ isC₂₋₁₀alkenyl-hetaryl. In another embodiment, R⁴ isC₂₋₁₀alkenylheteroalkyl. In another embodiment, R⁴ isC₂₋₁₀alkenylheterocyclcyl. In another embodiment, R⁴ is—C₂₋₁₀alkynylaryl. In another embodiment, R⁴ is C₂₋₁₀alkynylhetaryl. Inanother embodiment, R⁴ is C₂₋₁₀alkynylheteroalkyl. In anotherembodiment, R⁴ is C₂₋₁₀alkynylheterocylyl. In another embodiment, R⁴ isC₂₋₁₀alkynylC₃₋₈cycloalkyl. In another embodiment, R⁴ is heterocyclylC₁₋₁₀alkyl. In another embodiment, R⁴ is heterocyclylC₂₋₁₀alkenyl. Inanother embodiment, R⁴ is heterocyclyl-C₂₋₁₀alkynyl. In anotherembodiment, R⁴ is aryl-C₁₋₁₀alkyl. In another embodiment, R⁴ isaryl-C₂₋₁₀alkenyl. In another embodiment, R⁴ is aryl-C₂₋₁₀alkynyl. Inanother embodiment, R⁴ is aryl-heterocyclyl. In another embodiment, R⁴is hetaryl-C₁₋₁₀alkyl. In another embodiment, R⁴ ishetaryl-C₂₋₁₀alkenyl. In another embodiment, R⁴ is hetaryl-C₂₋₁₀alkynyl.In another embodiment, R⁴ is C₃₋₈cycloalkyl-C₁₋₁₀alkyl. In anotherembodiment, R⁴ is C₃₋₈cycloalkyl-C₂₋₁₀alkenyl. In another embodiment, R⁴is C₃₋₈cycloalkyl-C₂₋₁₀alkynyl.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a. and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, A″, C, 3-1,3-3, 3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″ when R⁴ is aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkyl-C₁₋₁₀alkyl, heterocyclyl, heterocyclyl C₁₋₁₀alkyl, orheteroalkyl, it is unsubstituted. In another embodiment, when R⁴ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent halo. In another embodiment, when R⁴ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —OH. In another embodiment, when R⁴ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —R³¹. In another embodiment, when R⁴ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —CF₃. In another embodiment, when R⁴ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —OCF. In another embodiment, when R⁴ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —OR³¹. In another embodiment, when R⁴ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —NR³¹R³². In another embodiment, when R⁴ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —NR³⁴R³⁵. In another embodiment, when R⁴ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —C(O)R³¹. In another embodiment, when R⁴ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent CO₂R³¹. In another embodiment, when R⁴ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —C(═O)NR³¹R³². In another embodiment, whenR⁴ is aryl, hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —C(═O)NR³⁴R³⁵. In another embodiment, when R⁴ is aryl,hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —NO₂. In another embodiment, when R⁴ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —CN. In another embodiment, when R⁴ isaryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —S(O)₀₋₂R³¹. In another embodiment, when R⁴is aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —SO₂NR³¹R³². In another embodiment, when R⁴is aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —SO₂NR³⁴R³⁵. In another embodiment, when R⁴is aryl, hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent NR³¹C(═O)R³². In another embodiment, when R⁴ is aryl,hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —NR³¹C(═O)OR³². In another embodiment, when R⁴ is aryl,hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —NR³¹C(═O)NR³²R³³. In another embodiment, when R⁴ is aryl,hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —NR³¹S(O)₀₋₂R³². In another embodiment, when R⁴ is aryl,hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —C(═S)OR³¹. In another embodiment, when R⁴ is aryl, hetaryl,C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —C(═O)SR³¹. In another embodiment, when R⁴ is aryl, hetaryl,C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl, heterocyclyl,heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substituted with one ormore independent —NR³¹C(═NR³²)NR³³R³². In another embodiment, when R⁴ isaryl, hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent, —NR³¹C(═NR³²)OR³³. In another embodiment, when R⁴ is aryl,hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —NR³¹C(═NR³²)SR³³. In another embodiment, when R⁴ is aryl,hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —OC(═O)OR³³. In another embodiment, when R⁴ is aryl,hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —OC(═O)NR³¹R³². In another embodiment, when R⁴ is aryl,hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —OC(═O)SR³¹. In another embodiment, when R⁴ is aryl,hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —SC(═O)OR³¹. In another embodiment, when R⁴ is aryl,hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,heterocyclyl, heterocyclyl C₁₋₁₀alkyl, or heteroalkyl, it is substitutedwith one or more independent —P(O)OR³¹OR³². In another embodiment, whenR⁴ is aryl, hetaryl, C₁₋₁₀alkyl, cycloalkyl, heterocyclyl, heteroalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkyl, heterocyclyl C₁₋₁₀alkyl, orC₃₋₈cycloalkyl-C₁₋₁₀alkyl, it is substituted with one or moreindependent —SC(═O)NR³¹R³².

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), B, C, or C″, R⁵is hydrogen. In another embodiment, R⁵ is halogen. In anotherembodiment, R⁵ is —OH. In another embodiment, R⁵ is —R³¹. In anotherembodiment, R⁵ is —CF₃. In another embodiment, R⁵ is —OCF₃. In anotherembodiment, R⁵ is —OR³¹. In another embodiment, R⁵ is —NR³¹R³². Inanother embodiment, R⁵ is —NR³⁴R³⁵. In another embodiment, R⁵ is—C(O)R³¹. In another embodiment, R⁵ is —CO₂R³¹. In another embodiment,R⁵ is —C(═O)NR³¹R³². In another embodiment, R⁵ is —C(═O)NR³⁴R³⁵. Inanother embodiment, R⁵ is —NO₂. In another embodiment, R⁵ is —CN. Inanother embodiment, R⁵ is —S(O)₂R³¹. In another embodiment, R⁵ is—SO₂NR³¹R³². In another embodiment, R⁵ is —SO₂NR³⁴R³⁵. In anotherembodiment, R⁵ is —NR³¹C(═O)R³². In another embodiment, R⁵ isNR³¹C(═O)OR³². In another embodiment, R⁵ is —NR³¹C(═O)NR³²R³³. Inanother embodiment, R⁵ is —NR³¹S(O)₀₋₂R³². In another embodiment, R⁵ is—C(═S)OR³¹. In another embodiment, R⁵ is —C(═O)SR³¹. In anotherembodiment, R⁵ is NR³¹C(═NR³²)NR³³R³². In another embodiment, R⁵ is—NR³¹C(═NR³²)OR³³. In another embodiment, R⁵ is —NR³¹C(═NR³²)SR³³. Inanother embodiment, R⁵ is —OC(═O)OR³³. In another embodiment, R⁵ is—OC(═O)NR³¹R³². In another embodiment, R⁵ is —OC(═O)SR³¹. In anotherembodiment, R⁵ is —SC(═O)OR³¹. In another embodiment, R⁵ isP(O)OR³¹OR³². In another embodiment, R⁵ is or —SC(═O)NR³¹R³²

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, A″, C, 3-1,3-3, 3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, R⁷ is hydrogen. In another embodiment, R⁷ is unsubstitutedC₁₋₁₀alkyl. In another embodiment, R⁷ is unsubstituted C₂₋₁₀alkenyl. Inanother embodiment, R⁷ is unsubstituted aryl. In another embodiment, R⁷is unsubstituted heteroaryl. In another embodiment, R⁷ is unsubstitutedheterocyclyl. In another embodiment, R⁷ is unsubstitutedC₃₋₁₀cycloalkyl. In another embodiment, R⁷ is C₁₋₁₀alkyl substituted byone or more independent R⁶. In another embodiment, R⁷ is C₂₋₁₀alkenylsubstituted by one or more independent R⁶. In another embodiment, R⁷ isaryl substituted by one or more independent R⁶. In another embodiment,R⁷ is heteroaryl substituted by one or more independent R⁶. In anotherembodiment, R⁷ is heterocyclyl substituted by one or more independentR⁶. In another embodiment, R⁷ is C₃₋₁₀cycloalkyl substituted by one ormore independent R⁶.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a. and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, A″, C, 3-1,3-3, 3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″″, R⁸ is hydrogen. In another embodiment, R⁸ is unsubstitutedC₁₋₁₀alkyl. In another embodiment, R⁸ is unsubstituted C₂₋₁₀alkenyl. Inanother embodiment, R⁸ is unsubstituted aryl. In another embodiment, R⁸is unsubstituted heteroaryl. In another embodiment, R⁸ is unsubstitutedheterocyclyl. In another embodiment, R⁸ is unsubstitutedC₃₋₁₀cycloalkyl. In another embodiment, R⁸ is C₁₋₁₀alkyl substituted byone or more independent R⁶. In another embodiment, R⁸ is C₂₋₁₀alkenylsubstituted by one or more independent R⁶. In another embodiment, R⁸ isaryl substituted by one or more independent R⁶. In another embodiment,R⁸ is heteroaryl substituted by one or more independent R⁶. In anotherembodiment, R⁸ is heterocyclyl substituted by one or more independentR⁶. In another embodiment, R⁸ is C₃₋₁₀cycloalkyl substituted by one ormore independent R⁶.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B (includingII-B-1 and II-B-2), III (including III-A and III-B), IV-A (includingIV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2), A, A″, C, 3-1,3-3, 3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, orN-3″, R⁶ is halo, In another embodiment, R⁶ is —OR³¹. In anotherembodiment, R⁶ is —SH. In another embodiment, R⁶ is NH₂. In anotherembodiment, R⁶ is —NR³⁴R³⁵. In another embodiment, R⁶ is —NR³¹R³². Inanother embodiment, R⁶ is CO₂R³¹. In another embodiment, R⁶ is —CO₂aryl.In another embodiment, R⁶ is —C(═O)NR³¹R³². In another embodiment, R⁶ isC(═O) NR³⁴R³⁵. In another embodiment, R⁶ is —NO₂. In another embodiment,R⁶ is —CN. In another embodiment, R⁶ is —S(O)₀₋₂ C₁₋₁₀alkyl. In anotherembodiment, R⁶ is —S(O)₀₋₂aryl. In another embodiment, R⁶ is—SO₂NR³⁴R³⁵. In another embodiment, R⁶ is —SO₂NR³¹R³². In anotherembodiment, R⁶ is C₁₋₁₀alkyl. In another embodiment, R⁶ is C₂₋₁₀alkenyl.In another embodiment, R⁶ is C₂₋₁₀alkynyl. In another embodiment, R⁶ isunsubstituted aryl-C₁₋₁₀alkyl. In another embodiment, R⁶ isunsubstituted aryl-C₂₋₁₀alkenyl. In another embodiment, R⁶ isunsubstituted aryl-C₂₋₁₀alkynyl. In another embodiment, R⁶ isunsubstituted hetaryl-C₁₋₁₀alkyl. In another embodiment, R⁶ isunsubstituted hetaryl-C₂₋₁₀alkenyl. In another embodiment, R⁶ isaryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, or hetaryl-C₂₋₁₀alkenyl substituted by one or moreindependent halo. In another embodiment, R⁶ is aryl-C₁₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, orhetaryl-C₂₋₁₀alkenyl substituted by one or more independent cyano. Inanother embodiment, R⁶ is aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, or hetaryl-C₂₋₁₀alkenylsubstituted by one or more independent nitro. In another embodiment, R⁶is aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, or hetaryl-C₂₋₁₀alkenyl substituted by one or moreindependent —OC₁₋₁₀alkyl. In another embodiment, R⁶ is aryl-C₁₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, orhetaryl-C₂₋₁₀alkenyl substituted by one or more independent —C₁₋₁₀alkyl.In another embodiment, R⁶ is aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, or hetaryl-C₂₋₁₀alkenylsubstituted by one or more independent —C₂₋₁₀alkenyl. In anotherembodiment, R⁶ is aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, or hetaryl-C₂₋₁₀alkenyl substituted by one or moreindependent —C₂₋₁₀alkynyl. In another embodiment, R⁶ is aryl-C₁₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, orhetaryl-C₂₋₁₀alkenyl substituted by one or more independent-(halo)C₁₋₁₀alkyl. In another embodiment, R⁶ is aryl-C₁₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, orhetaryl-C₂₋₁₀alkenyl substituted by one or more independent-(halo)C₂₋₁₀alkenyl. In another embodiment, R⁶ is aryl-C₁₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, orhetaryl-C₂₋₁₀alkenyl substituted by one or more independent-(halo)C₂₋₁₀alkynyl. In another embodiment, R⁶ is aryl-C₁₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, orhetaryl-C₂₋₁₀alkenyl substituted by one or more independent —COOH. Inanother embodiment, R⁶ is aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, or hetaryl-C₂₋₁₀alkenylsubstituted by one or more independent —C(═O)NR³¹R³². In anotherembodiment, R⁶ is aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, or hetaryl-C₂₋₁₀alkenyl substituted by one or moreindependent —C(═O)NR³⁴R³⁵. In another embodiment, R⁶ is aryl-C₁₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, orhetaryl-C₂₋₁₀alkenyl substituted by one or more independent —SO₂NR³⁴R³⁵.In another embodiment, R⁶ is aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, or hetaryl-C₂₋₁₀alkenylsubstituted by one or more independent —SO₂NR³¹R³². In anotherembodiment, R⁶ is aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, or hetaryl-C₂₋₁₀alkenyl substituted by one or moreindependent —NR³¹R³². In another embodiment, R⁶ is aryl-C₁₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, orhetaryl-C₂₋₁₀alkenyl substituted by one or more independent —NR³⁴R³⁵.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), III (including III-A and III-B), IV-A (including IV-A-1 andIV-A-2), or IV-B (including IV-B-1 and IV-B-2) A, A″, C, 3-1, 3-3, 3-4,3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1, N-3, N-1″, or N-3″, R⁹is H. In another embodiment, R⁹ is halo. In another embodiment, R⁹ is—OR³¹. In another embodiment, R⁹ is —SH. In another embodiment, R⁹ isNH₂. In another embodiment, R⁹ is —NR³⁴R³⁵. In another embodiment, R⁹ is—NR³¹R³². In another embodiment, R⁹ is —CO₂R³¹. In another embodiment,R⁹ is —CO₂aryl. In another embodiment, R⁹ is —C(═O)NR³¹R³². In anotherembodiment, R⁹ is —C(═O)NR³⁴R³⁵. In another embodiment, R⁹ is —NO₂. Inanother embodiment, R⁹ is —CN. In another embodiment, R⁹ is—S(O)₀₋₂C₁₋₁₀alkyl. In another embodiment, R⁹ is —S(O)₀₋₂aryl. Inanother embodiment, R⁹ is —SO₂NR³⁴R³⁵. In another embodiment, R⁹ is—SO₂NR³¹R³². In another embodiment, R⁹ is C₁₋₁₀alkyl. In anotherembodiment, R⁹ is C₂₋₁₀alkenyl. In another embodiment, R⁹ isC₂₋₁₀alkynyl. In another embodiment, R⁹ is unsubstitutedaryl-C₁₋₁₀alkyl. In another embodiment, R⁹ is unsubstitutedaryl-C₂₋₁₀alkenyl. In another embodiment, R⁹ is unsubstitutedaryl-C₂₋₁₀alkynyl. In another embodiment, R⁹ is unsubstitutedhetaryl-C₁₋₁₀alkyl. In another embodiment, R⁹ is unsubstitutedhetaryl-C₂₋₁₀alkenyl. In another embodiment, R⁹ is aryl-C₁₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, orhetaryl-C₂₋₁₀alkenyl substituted by one or more independent halo. Inanother embodiment, R⁹ is aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, or hetaryl-C₂₋₁₀alkenylsubstituted by one or more independent cyano. In another embodiment, R⁹is aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, or hetaryl-C₂₋₁₀alkenyl substituted by one or moreindependent nitro. In another embodiment, R⁹ is aryl-C₁₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, orhetaryl-C₂₋₁₀alkenyl substituted by one or more independent—OC₁₋₁₀alkyl. In another embodiment, R⁹ is aryl-C₁₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, orhetaryl-C₂₋₁₀alkenyl substituted by one or more independent —C₁₋₁₀alkyl.In another embodiment, R⁹ is aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, or hetaryl-C₂₋₁₀alkenylsubstituted by one or more independent —C₂₋₁₀alkenyl. In anotherembodiment, R⁹ is aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, or hetaryl-C₂₋₁₀alkenyl substituted by one or moreindependent —C₂₋₁₀alkynyl. In another embodiment, R⁹ is aryl-C₁₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, orhetaryl-C₂₋₁₀alkenyl substituted by one or more independent-(halo)C₁₋₁₀alkyl. In another embodiment, R⁹ is aryl-C₁₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, orhetaryl-C₂₋₁₀alkenyl substituted by one or more independent-(halo)C₂₋₁₀alkenyl. In another embodiment, R⁹ is aryl-C₁₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, orhetaryl-C₂₋₁₀alkenyl substituted by one or more independent-(halo)C₂₋₁₀alkynyl. In another embodiment, R⁹ is aryl-C₁₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, orhetaryl-C₂₋₁₀alkenyl substituted by one or more independent COOH. Inanother embodiment, R⁹ is aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, or hetaryl-C₂₋₁₀alkenylsubstituted by one or more independent —C(═O)NR³¹R³². In anotherembodiment, R⁹ is aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, or hetaryl-C₂₋₁₀alkenyl substituted by one or moreindependent —C(═O)NR³⁴R³⁵. In another embodiment, R⁹ is aryl-C₁₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, orhetaryl-C₂₋₁₀alkenyl substituted by one or more independent —SO₂NR³⁴R³⁵.In another embodiment, R⁹ is aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, or hetaryl-C₂₋₁₀alkenylsubstituted by one or more independent —SO₂NR³¹R³². In anotherembodiment, R⁹ is aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, or hetaryl-C₂₋₁₀alkenyl substituted by one or moreindependent —NR³¹R³². In another embodiment, R⁹ is aryl-C₁₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl, hetaryl-C₁₋₁₀alkyl, orhetaryl-C₂₋₁₀alkenyl substituted by one or more independent —NR³⁴R³⁵.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1 and II-A-2), II-B (including II-B-1 andII-B-2), III (including III-A and III-B), IV-A (including IV-A-1 andIV-A-2), IV-B (including IV-B-1 and IV-B-2), A, B (including B′ and B″),C, C, 3-1, 3-3, 3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1,N-3, N-1″, or N-3″, or N-3, R³¹ is H. In some embodiments, R³¹ isunsubstituted C₁₋₁₀alkyl. In some embodiments, R³¹ is substitutedC₁₋₁₀alkyl. In some embodiments, R³¹ is C₁₋₁₀alkyl substituted with oneor more aryl. In some embodiments, R³¹ is C₁₋₁₀alkyl substituted withone or more heteroalkyl. In some embodiments, R³¹ is C₁₋₁₀alkylsubstituted with one or more heterocyclyl. In some embodiments, R³¹ isC₁₋₁₀alkyl substituted with one or more hetaryl. In some embodiments,when R³¹ is C₁₋₁₀alkyl substituted with one or more aryl, each of saidaryl substituents is unsubstituted or substituted with one or more halo,—OH, C₁₋₁₀alkyl, —CF₃, —O-aryl, —OCF₃, —OC₁₋₁₀alkyl, —NH₂,—N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl), —NH(aryl), —NR³⁴R³⁵,—C(O)(C₁₋₁₀alkyl), —C(O)(C₁₋₁₀alkyl-aryl), —C(O)(aryl), —CO₂—C₁₋₁₀alkyl,—CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl, —C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl),—C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵, C(═O)NH₂, —OCF₃, O(C₁₋₁₀alkyl),—O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂aryl, —SO₂N(aryl),—SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or —SO₂NR³⁴R³⁵. Insome embodiments, when R³¹ is C₁₋₁₀alkyl substituted with one or moreheteroalkyl, each of said heteroalkyl group is unsubstituted orsubstituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃, —O-aryl,—OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl),—NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl), —C(O)(C₁₋₁₀alkyl-aryl),—C(O)(aryl), —CO₂—C₁₋₁₀alkyl, —CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl,—C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵,—C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl), —O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂,—CN, —S(O)₀₋₂ C₁₋₁₀alkyl, —S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂ aryl,—SO₂N(aryl), —SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or—SO₂NR³⁴R³⁵ substituents. In some embodiments, when R³¹ is C₁₋₁₀alkylsubstituted with one or more heterocyclyl, each of said heterocyclylgroup is unsubstituted or substituted with one or more halo, —OH,—C₁₋₁₀alkyl, —CF₃, —O-aryl, —OCF₃, —OC₁₋₁₀alkyl, —NH₂,—N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl), —NH(aryl), —NR³⁴R³⁵,—C(O)(C₁₋₁₀alkyl), C(O)(C₁₋₁₀alkyl-aryl), —C(O)(aryl),—CO₀₋₂—C₁₋₁₀alkyl, —CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl,—C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵,—C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl), —O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂,—CN, —S(O)₀₋₂C₁₋₁₀alkyl, —S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂aryl,—SO₂N(aryl), —SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or—SO₂NR³⁴R³⁵. In some embodiments, when R³¹ is C₁₋₁₀alkyl substitutedwith one or more hetaryl, each of said hetaryl group is unsubstituted orsubstituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃, —O-aryl,—OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl),—NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl), —C(O)(C₁₋₁₀alkyl-aryl),—C(O)(aryl), —CO₂-C₁₋₁₀alkyl, —CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl,—C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵,—C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl), —O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂,—CN, —S(O)₀₋₂C₁₋₁₀alkyl, —S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂ aryl,—SO₂N(aryl), —SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or—SO₂NR³⁴R³⁵. In some embodiments, when R³¹ is substituted C₁₋₁₀alkyl, itis substituted by a combination of aryl, heteroalkyl, heterocyclyl, orhetaryl groups.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1 and II-A-2), II-B (including II-B-1 andII-B-2), III (including III-A and III-B), IV-A (including IV-A-1 andIV-A-2), IV-B (including IV-B-1 and IV-B-2), A, B (including B′ and B″),C, 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, N−1, or N-3, R³² is H. In someembodiments, R³² is unsubstituted C₁₋₁₀alkyl. In some embodiments, R³²is substituted C₁₋₁₀alkyl. In some embodiments, R³² is C₁₋₁₀alkylsubstituted with one or more aryl. In some embodiments, R³² isC₁₋₁₀alkyl substituted with one or more heteroalkyl. In someembodiments, R³² is C₁₋₁₀alkyl substituted with one or moreheterocyclyl. In some embodiments, R³² is C₁₋₁₀alkyl substituted withone or more hetaryl. In some embodiments, when R³² is C₁₋₁₀alkylsubstituted with one or more aryl, each of said aryl group isunsubstituted or substituted with one or more halo, —OH, —C₁₋₁₀alkyl,—CF₃, —O-aryl, —OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl),—NH(C₁₋₁₀alkyl), —NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl),—C(O)(C₁₋₁₀alkyl-aryl), C(O)(aryl), —CO₂—C₁₋₁₀alkyl, —CO—C₁₋₁₀alkylaryl,—CO₂-aryl, —C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —C(═O)NH(C₁₋₁₀alkyl),—C(═O)NR³⁴R³⁵, —C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl), —O-aryl,—N(aryl)(C₁₋₁₀alkyl), —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂aryl, —SO₂N(aryl),—SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or —SO₂NR³⁴R³⁵. Insome embodiments, when R³² is C₁₋₁₀alkyl substituted with one or moreheteroalkyl, each of said heteroalkyl group is unsubstituted orsubstituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃, —O-aryl,—OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl),—NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl), —C(O)(C₁₋₁₀alkyl-aryl),—C(O)(aryl), —CO₂—C₁₋₁₀alkyl, —CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl,—C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵,—C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl), —O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂,—CN, —S(O)₀₋₂C₁₋₁₀alkyl, —S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂aryl,—SO₂N(aryl), —SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or—SO₂NR³⁴R³⁵. In some embodiments, when R³² is C₁₋₁₀alkyl substitutedwith one or more heterocyclyl, each of said heterocyclyl group isunsubstituted or substituted with one or more halo, —OH, —C₁₋₁₀alkyl,—CF₃, —O-aryl, —OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl),—NH(C₁₋₁₀alkyl), —NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl),—C(O)(C₁₋₁₀alkyl-aryl), —C(O)(aryl), —CO₂—C₁₋₁₀alkyl,—CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl, —C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl),—C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵, C(═O)NH₂, —OCF₃, O(C₁₋₁₀alkyl),—O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂ aryl, —SO₂N(aryl),—SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or —SO₂NR³⁴R³⁵. Insome embodiments, when R³² is C₁₋₁₀alkyl substituted with one or morehetaryl, each of said hetaryl group is unsubstituted or substituted withone or more halo, —OH, —C₁₋₁₀alkyl, —CF₃, —O-aryl, —OCF₃, OC₁₋₁₀alkyl,—NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl), —NH(aryl), —NR³⁴R³⁵,C(O)(C₁₋₁₀alkyl), —C(O)(C₁₋₁₀alkyl-aryl), —C(O)(aryl), —CO₂—C₁₋₁₀alkyl,—CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl, —C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl),—C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵, C(═O)NH₂, —OCF₃, O(C₁₋₁₀alkyl),—O-aryl, —N(aryl)(C₁₋₁₀alkyl), NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂ aryl, —SO₂N(aryl),—SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or —SO₂NR³⁴R³⁵. Insome embodiments, when R³² is substituted C₁₋₁₀alkyl, it is substitutedby a combination of aryl, heteroalkyl, heterocyclyl, or hetaryl groups.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1 and II-A-2), II-B (including II-B-1 andII-B-2), III (including III-A and III-B), IV-A (including IV-A-1 andIV-A-2), IV-B (including IV-B-1 and IV-B-2), A, B (including B′ and B″),C, 3-1, 3-3, 3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N—, N-3,N-1″, or N-3″, R³³ is unsubstituted C₁₋₁₀alkyl. In some embodiments, R³³is substituted C₁₋₁₀alkyl. In some embodiments, R³³ is C₁₋₁₀alkylsubstituted with one or more aryl. In some embodiments, R³³ isC₁₋₁₀alkyl substituted with one or more heteroalkyl. In someembodiments, R³³ is C₁₋₁₀alkyl substituted with one or moreheterocyclyl. In some embodiments, R³³ is C₁₋₁₀alkyl substituted withone or more hetaryl. In some embodiments, when R³³ is C₁₋₁₀alkylsubstituted with one or more aryl, each of said aryl group isunsubstituted or substituted with one or more halo, —OH, —C₁₋₁₀alkyl,—CF₃, —O-aryl, —OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl),—NH(C₁₋₁₀alkyl), —NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl),—C(O)(C₁₋₁₀alkyl-aryl), —C(O)(aryl), —CO₂—C₁₋₁₀alkyl,—CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl, —C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl),—C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵, C(═O)NH₂, —OCF₃, O(C₁₋₁₀alkyl),—O-aryl, N(aryl)(C₁₋₁₀alkyl), —NO₂, —CN, —S(O)₂C₁₋₁₀alkyl,—S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂aryl, —SO₂N(aryl),—SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or —SO₂NR³⁴R³⁵. Insome embodiments, when R³³ is C₁₋₁₀alkyl substituted with one or moreheteroalkyl, each of said heteroalkyl group is unsubstituted orsubstituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃, —O-aryl,—OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl),—NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl), —C(O)(C₁₋₁₀alkyl-aryl),C(O)(aryl), CO₂—C₁₋₁₀alkyl, —CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl,—C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵,—C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl), —O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂,—CN, —S(O)₀₋₂C₁₋₁₀alkyl, —S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂aryl,—SO₂N(aryl), —SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or—SO₂NR³⁴R³⁵. In some embodiments, when R³³ is C₁₋₁₀alkyl substitutedwith one or more heterocyclyl, each of said heterocyclyl group isunsubstituted or substituted with one or more halo, —OH, —C₁₋₁₀alkyl,—CF₃, —O-aryl, —OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl),—NH(C₁₋₁₀alkyl), —NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl),—C(O)(C₁₋₁₀alkyl-aryl), —C(O)(aryl), —CO₂—C₁₋₁₀alkyl,—CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl, —C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl),—C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵, C(═O)NH₂, —OCF₃, O(C₁₋₁₀alkyl),—O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂ aryl, —SO₂N(aryl),—SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or —SO₂NR³⁴R³⁵. Insome embodiments, when R³³ is C₁₋₁₀alkyl substituted with one or morehetaryl, each of said hetaryl group is unsubstituted or substituted withone or more halo, —OH, —C₁₋₁₀alkyl, —CF₃, —O-aryl, —OCF₃, —OC₁₋₁₀alkyl,—NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —NH(C₁₋₁₀alkyl), —NH(aryl), —NR³⁴R³⁵,—C(O)(C₁₋₁₀alkyl), —C(O)(C₁₋₁₀alkyl-aryl), —C(O)(aryl), —CO₂—C₁₋₁₀alkyl,—CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl, —C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl),—C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵, —C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl),—O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂ aryl, —SO₂N(aryl),—SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or —SO₂NR³⁴R³⁵. Insome embodiments, when R³³ is substituted C₁₋₁₀alkyl, it is substitutedby a combination of aryl, heteroalkyl, heterocyclyl, or hetaryl groups.

In various embodiments of compounds of Formula I′-A′, I (including I-Aand I-B), II-A (including II-A-1 and II-A-2), II-B (including II-B-1 andII-B-2), III (including III-A and III-B), IV-A (including IV-A-1 andIV-A-2), IV-B (including IV-B-1 and IV-B-2), A, B (including B′ and B″),C, 3-1, 3-3, 3-4, 3-5, 3-6, C″, 3-1″, 3-3″, 3-4″, 3-5″, or 3-6″, N-1,N-3, N-1″, or N-3″, R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or—SO₂NR³⁴R³⁵, are taken together with the nitrogen atom to which they areattached to form a 3-10 membered saturated or unsaturated ring; whereinsaid ring is independently unsubstituted or is substituted by one ormore —NR³¹R³², hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, orO-aryl, and wherein said 3-10 membered saturated or unsaturated ringindependently contains 0, 1, or 2 more heteroatoms in addition to thenitrogen.

In some embodiments, the R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or—SO₂NR³⁴R³⁵, are taken together with the nitrogen atom to which they areattached to form:

In another embodiment, X₁ is C—NH₂.

In various embodiments, X₁ is C—NH—R⁴, where —NH—R⁴ is:

In one aspect, the invention provides a compound of Formula II-A-1:

or a pharmaceutically acceptable salt thereof, wherein:

X₁ is N or C-E¹ and X₂ is N; or X₁ is NH or CH-E¹ and X₂ is C;

R₁ is hydrogen, -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl,-L-C₁₋₁₀alkyl-C₃₋₈cycloalkyl, -L-aryl, -L-heteroaryl, -L-C₁₋₁₀alkylaryl,-L-C₁₋₁₀alkylhetaryl, -L-C₁₋₁₀alkylheterocylyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₂₋₁₀alkenyl-C₃-cycloalkyl,-L-C₂₋₁₀alkynyl-C₃₋₈cycloalkyl, -L-heteroalkyl, -L-heteroalkylaryl,-L-heteroalkylheteroaryl, -L-heteroalkyl-heterocylyl,-L-heteroalkyl-C₃-cycloalkyl, -L-aralkyl, -L-heteroaralkyl, or-L-heterocyclyl, each of which is unsubstituted or substituted by one ormore independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

M₁ is benzoxazolyl substituted with -(W²)_(k)-R²;

k is 0 or 1;

E¹ and E² are independently -(W¹)_(j)-R⁴;

j in E¹ or j in E², is independently 0 or 11;

W¹ is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)S(O)—, —N(R⁷)S(O)₂, —C(O)O—, —CH(R⁷)N(C(O)OR⁸)—,—CH(R⁷)N(C(O)R⁸)—, CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—,—CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—;

W² is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—,—N(R⁷)C(O)N(R⁸)—, —N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—,—CH(R⁷)N(C(O)OR⁸)—, —CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—,—CH(R⁷)C(O)N(R⁸)—, —CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or—CH(R⁷)N(R⁸)S(O)₂—;

R³ and R⁴ are independently hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³², aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₁₋₁₀alkyl-C₂₋₁₀alkenyl, C₁₋₁₀alkyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylaryl,C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₂₋₁₀alkenyl-C₁₋₁₀alkyl, C₂₋₁₀alkynyl-C₁₋₁₀alkyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxy-C₂₋₁₀alkenyl, C₁₋₁₀alkoxy-C₂₋₁₀alkynyl,heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,aryl-C₂₋₁₀alkynyl, aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, hetaryl C₂₋₁₀alkynyl, hetaryl C₃₋₈cycloalkyl,heteroalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein eachof said aryl or heteroaryl moiety is unsubstituted or is substitutedwith one or more independent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵,—NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², orSC(═O)NR³¹R³² and wherein each of said alkyl, cycloalkyl, heterocyclyl,or heteroalkyl moiety is unsubstituted or substituted with one or morehalo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³², —NR³⁴R³⁵,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R, or —C(═O)NR³¹R³²;

R² is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², SC(═O)NR³¹R³²,bicyclic aryl, substituted monocyclic aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkyl C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₂₋₁₀alkyl-monocyclic aryl, monocyclic aryl-C₂₋₁₀alkyl,C₁₋₁₀alkylbicycloaryl, bicycloaryl-C₁₋₁₀alkyl, substitutedC₁₋₁₀alkylaryl, substituted aryl-C₁₋₁₀alkyl, C₁₋₁₀alkylhetaryl,C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkenyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxy C₁₋₁₀alkyl,C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl, heterocyclyl,heterocyclyl C₁₋₁₀alkyl, heterocyclylC₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkenyl, aryl C₂₋₁₀alkynyl,aryl-heterocyclyl, hetaryl C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl,hetaryl-C₂₋₁₀alkynyl, hetaryl C₃₋₈cycloalkyl, hetaryl-heteroalkyl, orhetaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroarylmoiety is unsubstituted, or wherein each of bicyclic aryl, heteroarylmoiety or monocyclic aryl moiety is substituted with one or moreindependent halo, —OH, —R³¹, —CF₃, OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₂R³¹,—SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

R³¹, R³², and R³³, in each instance, are independently H or C₁₋₁₀alkyl,wherein the C₁₋₁₀alkyl is unsubstituted or is substituted with one ormore aryl, heteroalkyl, heterocyclyl, or hetaryl group, wherein each ofsaid, aryl, heteroalkyl, heterocyclyl, or hetaryl group is unsubstitutedor is substituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃,—O-aryl, —OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl),—NH(C₁₋₁₀alkyl), —NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl),—C(O)(C₁₋₁₀alkyl-aryl), —C(O)(aryl), —CO₂—C₁₋₁₀alkyl,—CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl, —C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl),—C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵, —C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl),—O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂aryl, —SO₂N(aryl),—SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or —SO₂NR³⁴R³⁵;

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen;

R⁷ and R⁸ are each independently hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,aryl, heteroaryl, heterocyclyl or C₃₋₁₀cycloalkyl, each of which exceptfor hydrogen is unsubstituted or is substituted by one or moreindependent R⁶; and

R⁶ is halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, CO₂aryl—C(═O)NR³¹R³², C(═O) NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, eachof which is unsubstituted or is substituted with one or more independenthalo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², or—NR³⁴R³⁵.

In another aspect, the invention provides a compound of Formula II-A-1or a pharmaceutically acceptable salt thereof wherein:

E² is —H; X₁ and X₂ are N;

R₁ is -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkylheterocylyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

R³ is hydrogen, —OH, —OR³¹, —NR³¹R³², —C(O)R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, aryl, hetaryl, C₁₋₄alkyl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, orheterocyclyl, wherein each of said aryl or heteroaryl moiety isunsubstituted or is substituted with one or more independent alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³², and wherein each of saidalkyl, cycloalkyl, or heterocyclyl moiety is unsubstituted or issubstituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

-(W²)_(k)- is —NR⁷—, —N(R⁷)C(O)— or —N(R⁷)S(O)₂—;

k is 0 or 1;

R² is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,bicyclic aryl, substituted monocyclic aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₂₋₁₀alkyl-monocyclic aryl, monocyclic aryl-C₂₋₁₀alkyl,C₁₋₁₀alkylbicycloaryl, bicycloaryl-C₁₋₁₀alkyl, substitutedC₁₋₁₀alkylaryl, substituted aryl-C₁₋₁₀alkyl, C₁₋₁₀alkylhetaryl,C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkenyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxy C₁₋₁₀alkyl,C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl, heterocyclyl,heterocyclyl C₁₋₁₀alkyl, heterocyclylC₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl,hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl, hetaryl-heteroalkyl, orhetaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroarylmoiety is unsubstituted, or wherein each of bicyclic aryl, heteroarylmoiety or monocyclic aryl moiety is substituted with one or moreindependent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹,—SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

R³¹, R³², and R³³, in each instance, are independently H or C₁₋₁₀alkyl,wherein the C₁₋₁₀alkyl is unsubstituted or is substituted with one ormore aryl, heteroalkyl, heterocyclyl, or hetaryl group, wherein each ofsaid alkyl, aryl, heteroalkyl, heterocyclyl, or hetaryl group isunsubstituted or is substituted with one or more halo, —OH, —C₁₋₁₀alkyl,—CF₃, —O-aryl, —OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl),—NH(C₁₋₁₀alkyl), —NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl),—C(O)(C₁₋₁₀alkyl-aryl), —C(O)(aryl), —CO₂—C₁₋₁₀alkyl,—CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl, —C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl),—C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵, —C(═O)NH₂, —OCF₃, —O(C₁₋₁₀alkyl),—O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂ aryl, —SO₂N(aryl),—SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or —SO₂NR³⁴R³⁵;

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen;

R⁷ is hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, aryl, heteroaryl, heterocyclylor C₃₋₁₀cycloalkyl, each of which except for hydrogen is unsubstitutedor is substituted by one or more independent R⁶; and

R⁶ is halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, eachof which is unsubstituted or is substituted with one or more independenthalo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², orNR³⁴R³⁵.

In yet another aspect, the invention provides a compound of FormulaII-A-1 or a pharmaceutically acceptable salt thereof wherein:

E² is —H; X₁ and X₂ are N;

R₁ is -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkylheterocylyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

R³ is hydrogen, —OH, —OR³¹, —NR³¹R³², —C(O)R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, aryl, hetaryl, C₁₋₄alkyl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, orheterocyclyl, wherein each of said aryl or heteroaryl moiety isunsubstituted or is substituted with one or more independent alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³² and wherein each of saidalkyl, cycloalkyl, or heterocyclyl moiety is unsubstituted or issubstituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, r C(═O)NR³¹R³²;

-(W²)_(k)- is —NH—, —N(H)C(O)— or N(H)S(O)₂—;

R² is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,bicyclic aryl, substituted monocyclic aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₂₋₁₀alkyl-monocyclic aryl, monocyclic aryl-C₂₋₁₀alkyl,C₁₋₁₀alkylbicycloaryl, bicycloaryl-C₁₋₁₀alkyl, substitutedC₁₋₁₀alkylaryl, substituted aryl-C₁₋₁₀alkyl, C₁₋₁₀alkylhetaryl,C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkenyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxy C₁₋₁₀alkyl,C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl, heterocyclyl,heterocyclyl C₁₋₁₀alkyl, heterocyclylC₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl,hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl, hetaryl-heteroalkyl, orhetaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroarylmoiety is unsubstituted, or wherein each of bicyclic aryl, heteroarylmoiety or monocyclic aryl moiety is substituted with one or moreindependent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₂R³¹,—SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

R³¹, R³², and R³³, in each instance, are independently H or C₁₋₁₀alkyl,wherein the C₁₋₁₀alkyl is unsubstituted; and

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen.

In a further aspect, the invention provides a compound of Formula II-A-1or a pharmaceutically acceptable salt thereof wherein:

E² is —H;

X₁ and X₂ are N;

R₁ is -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkylheterocylyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

R³ is hydrogen, —OH, —OR³¹, —NR³¹R³², —C(O)R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, aryl, hetaryl, C₁₋₄alkyl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, orheterocyclyl, wherein each of said aryl or heteroaryl moiety isunsubstituted or is substituted with one or more independent alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³² and wherein each of saidalkyl, cycloalkyl, or heterocyclyl moiety is unsubstituted or issubstituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

-(W²)_(k)- is —NH—, —N(H)C(O)— or N(H)S(O)₂—;

R² is hydrogen, halogen, —OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹R³², C(═O)NR³⁴R³⁵, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,bicyclic aryl, substituted monocyclic aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₂₋₁₀alkyl-monocyclic aryl, monocyclic aryl-C₂₋₁₀alkyl,C₁₋₁₀alkylbicycloaryl, bicycloaryl-C₁₋₁₀alkyl, substitutedC₁₋₁₀alkylaryl, substituted aryl-C₁₋₁₀alkyl, C₁₋₁₀alkylhetaryl,C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkenyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxy C₁₋₁₀alkyl,C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl, heterocyclyl,heterocyclyl C₁₋₁₀alkyl, heterocyclylC₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl,hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl, hetaryl-heteroalkyl, orhetaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroarylmoiety is unsubstituted, or wherein each of bicyclic aryl, heteroarylmoiety or monocyclic aryl moiety is substituted with one or moreindependent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵,—C(O)R³¹, CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₂R³¹,—SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

R³¹, R³², and R³³, in each instance, are independently H or C₁₋₁₀alkyl,wherein the C₁₋₁₀alkyl is unsubstituted; and

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen.

In another aspect, the compound of Formula II-A-1 is a compound ofFormula II-A-1a:

or a pharmaceutically acceptable salt thereof, wherein:

E² is —H; X₁ and X₂ are N;

R₁ is -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkylheterocylyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

R³ is hydrogen, —OH, —OR³¹, —NR³¹R³², —C(O)R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, aryl, hetaryl, C₁₋₄alkyl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, orheterocyclyl, wherein each of said aryl or heteroaryl moiety isunsubstituted or is substituted with one or more independent alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³², and wherein each of saidalkyl, cycloalkyl, or heterocyclyl moiety is unsubstituted or issubstituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

-(W²)_(k)- is —NH—, —N(H)C(O)— or N(H)S(O)₂—;

R² is hydrogen, halogen, —OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,bicyclic aryl, substituted monocyclic aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₂₋₁₀alkyl-monocyclic aryl, monocyclic aryl-C₂₋₁₀alkyl,C₁₋₁₀alkylbicycloaryl, bicycloaryl-C₁₋₁₀alkyl, substitutedC₁₋₁₀alkylaryl, substituted aryl-C₁₋₁₀alkyl, C₁₋₁₀alkylhetaryl,C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, heterocyclyl,heterocyclyl C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl,hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein each of saidbicyclic aryl or heteroaryl moiety is unsubstituted, or wherein each ofbicyclic aryl, heteroaryl moiety or monocyclic aryl moiety issubstituted with one or more independent halo, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³², and wherein each of saidalkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstitutedor is substituted with one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—O-aryl, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or—C(═O)NR³¹R³²;

R³¹, R³², and R³³, in each instance, are independently H or C₁₋₁₀alkyl,wherein the C₁₋₁₀alkyl is unsubstituted; and

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen.

In another aspect, the invention provides a compound of Formula II-A-1:

or a pharmaceutically acceptable salt thereof, wherein:

E² is —H; X₁ is CH and X₂ is N;

R₁ is -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkylheterocylyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

R³ is hydrogen, —OH, —OR³¹, —NR³¹R³², —C(O)R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, aryl, hetaryl, C₁₋₄alkyl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, orheterocyclyl, wherein each of said aryl or heteroaryl moiety isunsubstituted or is substituted with one or more independent alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³² and wherein each of saidalkyl, cycloalkyl, or heterocyclyl moiety is unsubstituted or issubstituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

-(W²)_(k)- is —NR⁷—, —N(R⁷)C(O)— or —N(R⁷)S(O)₂—;

k is 0 or 1;

R² is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²bicyclic aryl, substituted monocyclic aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₂₋₁₀alkyl-monocyclic aryl, monocyclic aryl-C₂₋₁₀alkyl,C₁₋₁₀alkylbicycloaryl, bicycloaryl-C₁₋₁₀alkyl, substitutedC₁₋₁₀alkylaryl, substituted aryl-C₁₋₁₀alkyl, C₁₋₁₀alkylhetaryl,C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkenyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxy C₁₋₁₀alkyl,C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl, heterocyclyl,heterocyclyl C₁₋₁₀alkyl, heterocyclylC₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl,hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl, hetaryl-heteroalkyl, orhetaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroarylmoiety is unsubstituted, or wherein each of bicyclic aryl, heteroarylmoiety or monocyclic aryl moiety is substituted with one or moreindependent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, S(O)₀₋₂R³¹,—SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³¹R³², —C(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

R³¹, R³², and R³³, in each instance, are independently H or C₁₋₁₀alkyl,wherein the C₁₋₁₀alkyl is unsubstituted or is substituted with one ormore aryl, heteroalkyl, heterocyclyl, or hetaryl group, wherein each ofsaid aryl, heteroalkyl, heterocyclyl, or hetaryl group is unsubstitutedor is substituted with one or more halo, —OH, —C₁₋₁₀alkyl, —CF₃,—O-aryl, OCF₃, —OC₁₋₁₀alkyl, —NH₂, —N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl),—NH(C₁₋₁₀alkyl), —NH(aryl), —NR³⁴R³⁵, —C(O)(C₁₋₁₀alkyl),C(O)(C₁₋₁₀alkyl-aryl), —C(O)(aryl), —CO₂—C₁₋₁₀alkyl,—CO₂—C₁₋₁₀alkylaryl, —CO₂-aryl, —C(═O)N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl),—C(═O)NH(C₁₋₁₀alkyl), —C(═O)NR³⁴R³⁵, C(═O)NH₂, —OCF₃, O(C₁₋₁₀alkyl),—O-aryl, —N(aryl)(C₁₋₁₀alkyl), —NO₂, —CN, —S(O)₀₋₂C₁₋₁₀alkyl,—S(O)₀₋₂C₁₋₁₀alkylaryl, —S(O)₀₋₂ aryl, —SO₂N(aryl),—SO₂N(C₁₋₁₀alkyl)(C₁₋₁₀alkyl), —SO₂NH(C₁₋₁₀alkyl) or —SO₂NR³⁴R³⁵;

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen;

R⁷ is hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, aryl, heteroaryl, heterocyclylor C₃₋₁₀cycloalkyl, each of which except for hydrogen is unsubstitutedor is substituted by one or more independent R⁶; and

R⁶ is halo, —OR³¹, —SH, —NH₂, —NR³⁴R³⁵, —NR³¹R³², —CO₂R³¹, —CO₂aryl—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂ C₁₋₁₀alkyl,—S(O)₀₋₂aryl, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, aryl-C₁₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, eachof which is unsubstituted or is substituted with one or more independenthalo, cyano, nitro, —OC₁₋₁₀alkyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —SO₂NR³⁴R³⁵, —SO₂NR³¹R³², —NR³¹R³², orNR³⁴R³⁵;

In yet another aspect, the invention provides a compound of FormulaII-A-1 or a pharmaceutically acceptable salt thereof wherein:

E² is —H; X₁ is CH and X₂ is N;

R₁ is -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkylheterocylyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

R³ is hydrogen, —OH, —OR³¹, —NR³¹R³², —C(O)R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, aryl, hetaryl, C₁₋₄alkyl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, orheterocyclyl, wherein each of said aryl or heteroaryl moiety isunsubstituted or is substituted with one or more independent alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³² and wherein each of saidalkyl, cycloalkyl, or heterocyclyl moiety is unsubstituted or issubstituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

-(W²)_(k)- is —NH—, —N(H)C(O)— or N(H)S(O)₂—;

R² is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²bicyclic aryl, substituted monocyclic aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₂₋₁₀alkyl-monocyclic aryl, monocyclic aryl-C₂₋₁₀alkyl,C₁₋₁₀alkylbicycloaryl, bicycloaryl-C₁₋₁₀alkyl, substitutedC₁₋₁₀alkylaryl, substituted aryl-C₁₋₁₀alkyl, C₁₋₁₀alkylhetaryl,C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₂₋₁₀alkenylaryl,C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkenyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxy C₁₋₁₀alkyl,C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl, heterocyclyl,heterocyclyl C₁₋₁₀alkyl, heterocyclylC₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl,hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl, hetaryl-heteroalkyl, orhetaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroarylmoiety is unsubstituted, or wherein each of bicyclic aryl, heteroarylmoiety or monocyclic aryl moiety is substituted with one or moreindependent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₂R³¹,—SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl,heterocyclyl, or heteroalkyl moiety is unsubstituted or is substitutedwith one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

R³¹, R³², and R³³, in each instance, are independently H or C₁₋₁₀alkyl,wherein the C₁₋₁₀alkyl is unsubstituted; and

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen.

In a further aspect, the invention provides a compound of Formula II-A-1or a pharmaceutically acceptable salt thereof wherein:

E² is —H; X₁ is CH and X₂ is N;

R₁ is -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkylheterocylyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

R³ is hydrogen, —OH, —OR³¹, —NR³¹R³², —C(O)R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, aryl, hetaryl, C₁₋₄alkyl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, orheterocyclyl, wherein each of said aryl or heteroaryl moiety isunsubstituted or is substituted with one or more independent alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³² and wherein each of saidalkyl, cycloalkyl, or heterocyclyl moiety is unsubstituted or issubstituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

-(W²)_(k)- is —NH—, —N(H)C(O)— or N(H)S(O)₂—;

R² is hydrogen, halogen, —OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, S(O)_(o)R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,bicyclic aryl, substituted monocyclic aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl,C₂₋₁₀alkyl-monocyclic aryl, monocyclic aryl-C₂₋₁₀alkyl,C₁₋₁₀alkylbicycloaryl, bicycloaryl-C₁₋₁₀alkyl, substitutedC₁₋₁₀alkylaryl, substituted aryl-C₁₋₁₀alkyl, C₁₋₁₀alkylhetaryl,C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₂₋₁₀alkenylaryl,C₂₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocyclcyl,C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl,C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkenyl-C₃₋₈cycloalkyl,C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxy C₁₋₁₀alkyl,C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl, heterocyclyl,heterocyclyl C₁₋₁₀alkyl, heterocyclylC₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl,hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl, hetaryl-heteroalkyl, orhetaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroarylmoiety is unsubstituted, or wherein each of bicyclic aryl, heteroarylmoiety or monocyclic aryl moiety is substituted with one or moreindependent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₂R³¹,—SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³²—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹R³² and wherein each of said alkyl, cycloalkyl, heterocyclyl,or heteroalkyl moiety is unsubstituted or is substituted with one ormore halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³², —NR³⁴R³⁵,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R, or —C(═O)NR³¹R³²;

R³¹, R³², and R³³, in each instance, are independently H or C₁₋₁₀alkyl,wherein the C₁₋₁₀alkyl is unsubstituted; and

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen.

In another aspect, the compound of Formula II-A-1 is a compound ofFormula II-A-1a:

or a pharmaceutically acceptable salt thereof, wherein: E² is —H; X₁ isCH and X₂ is N;

R₁ is -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkylheterocylyl, or-L-heterocyclyl, each of which is unsubstituted or is substituted by oneor more independent R³;

L is absent, —(C═O)—, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—,—S(O)₂N(R³¹)—, or —N(R³¹)—;

R³ is hydrogen, —OH, —OR³¹, —NR³¹R³², —C(O)R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, aryl, hetaryl, C₁₋₄alkyl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, orheterocyclyl, wherein each of said aryl or heteroaryl moiety isunsubstituted or is substituted with one or more independent alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³² and wherein each of saidalkyl, cycloalkyl, or heterocyclyl moiety is unsubstituted or issubstituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³²,—NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²;

-(W²)_(k)- is —NH—, —N(H)C(O)— or —N(H)S(O)₂—;

R² is hydrogen, halogen, —OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹R³², C(═O)NR³⁴R³⁵, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,bicyclic aryl, substituted monocyclic aryl, hetaryl, C₁₋₁₀alkyl,C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl,C₂₋₁₀alkyl-monocyclic aryl, monocyclic aryl-C₂₋₁₀alkyl,C₁₋₁₀alkylbicycloaryl, bicycloaryl-C₁₋₁₀alkyl, substitutedC₁₋₁₀alkylaryl, substituted aryl-C₁₋₁₀alkyl, C₁₋₁₀alkylhetaryl,C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, heterocyclyl,heterocyclyl C₁₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl,hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein each of saidbicyclic aryl or heteroaryl moiety is unsubstituted, or wherein each ofbicyclic aryl, heteroaryl moiety or monocyclic aryl moiety issubstituted with one or more independent halo, —OH, —R³¹, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³²,—C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³², and wherein each of saidalkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstitutedor is substituted with one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹,—O-aryl, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R, or—C(═O)NR³¹R³²;

R³¹, R³², and R³³, in each instance, are independently H or C₁₋₁₀alkyl,wherein the C₁₋₁₀alkyl is unsubstituted; and

R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are takentogether with the nitrogen atom to which they are attached to form a3-10 membered saturated or unsaturated ring; wherein said ring isindependently unsubstituted or is substituted by one or more —NR³¹R³²,hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and whereinsaid 3-10 membered saturated or unsaturated ring independently contains0, 1, or 2 more heteroatoms in addition to the nitrogen.

B. Reaction Schemes

The compounds disclosed herein may be prepared by the routes describedbelow. Materials used herein are either commercially available orprepared by synthetic methods generally known in the art. These schemesare not limited to the compounds listed or by any particularsubstituents employed for illustrative purposes. Numbering does notnecessarily correspond to that of claims or other tables.

In one embodiment, compounds are synthesized by condensing afunctionalized heterocycle A-1 with formamide, to provide apyrazolopyrimidine A-2. The pyrazolopyrimidine is treated withN-iodosuccinimide, which introduces an iodo substituent in the pyrazolering as in A-3. The R₁ substituent is introduced by reacting thepyrazolopyrimidine A3 with a compound of Formula R₁-Lg in the presenceof a base such as potassium carbonate to produce a compound of FormulaA-4. Other bases that are suitable for use in this step include but arenot limited to sodium hydride and potassium t-butoxide. The compound ofFormula R₁-Lg has a moiety R₁ as defined for R₁ of a compound of FormulaI′-A′, and wherein Lg is an appropriate leaving group such as halide(including bromo, iodo, and chloro), tosylate, or other suitable leavinggroup,

The substituents corresponding to M₁ are thereafter introduced byreacting aryl or hetaryl boronic acids with the compound of Formula A-4to obtain compound A-5.

Alternatively, Mitsunobu chemistry can be used to obtain alkylatedpyrazolopyrimidine A-4, as shown in Scheme A-1. IodopyrazolopyrimidineA-3 is reacted with a suitable alcohol, in the presence oftriphenylphosphine and diisopropylazodicarboxylate (DIAD) to producepyrazolopyrimidine A-4.

The compounds of the invention may be synthesized via a reaction schemerepresented generally in Scheme B. The synthesis proceeds via coupling acompound of Formula A with a compound of Formula B to yield a compoundof Formula C. The coupling step is typically catalyzed by using, e.g., apalladium catalyst, including but not limited to palladium tetrakis(triphenylphosphine). The coupling is generally performed in thepresence of a suitable base, a nonlimiting example being sodiumcarbonate. One example of a suitable solvent for the reaction is aqueousdioxane.

A compound of Formula A for use in Scheme B has a structure of FormulaA, wherein T₁ is triflate or halo (including bromo, chloro, and iodo),and wherein R₁, X₁, X₂, X₃, R₃₁ and R₃₂ are defined as for a compound ofFormula I′-A′. For boronic acids and acid derivatives as depicted inFormula B, M is either M₁ or M₂. M₁ is defined as for a compound ofFormula I′-A′. For example, M₁ can be a 5-benzoxazolyl or a6-benzoxazolyl moiety, including but not limited to those M₁ moietiesdisclosed herein. M₂ is a moiety which is synthetically transformed toform M₁, after the M₂ moiety has been coupled to the bicyclic core ofthe compound of Formula A.

For a compound of Formula B, G is hydrogen or R_(G1), wherein R_(G1) isalkyl, alkenyl, or aryl. Alternatively, B(OG)₂ is taken together to forma 5- or 6-membered cyclic moiety. In some embodiments, the compound ofFormula B is a compound having a structure of Formula E:

wherein G is H or R_(G1); R_(G1) is alkyl, alkenyl, or aryl.Alternatively,

forms a 5- or 6-membered cyclic moiety; and R₂ is a R_(G2) moiety,wherein the R_(G2) moiety is H, acyl, or an amino protecting groupincluding but not limited to tert-butyl carbamate (Boc), carbobenzyloxy(Cbz), benzyl (Bz), fluorenylmethyloxycarbonyl (FMOC), p-methoxybenzyl(PMB), and the like.

In some embodiments, a compound of Formula B is a compound of FormulaB′, wherein G is R_(G1). or a compound of Formula B″, wherein G ishydrogen. Scheme C depicts an exemplary scheme for synthesizing acompound of Formula B′ or, optionally, Formula B″ for use in ReactionScheme C. This reaction proceeds via reacting a compound of Formula Dwith a trialkyl borate or a boronic acid derivative to produce acompound of Formula B′. The reaction is typically run a solvent such asdioxane or tetrahydrofuran. The trialkyl borate includes but is notlimited to triisopropyl borate and the boronic acid derivative includesbut is not limited to bis(pinacolato)diboron.

When the reaction is performed with trialkyl borate, a base such asn-butyllithium is first added to the compound of Formula D to generatean anion, prior to the addition of the borate. When the reaction isperformed with a boronic acid derivative such as bis(pinacolato)diboron,a palladium catalyst and a base is used. Typical palladium catalystsinclude but is not limited to palladium chloride(diphenylphosphino)ferrocene). A suitable base includes but is notlimited to potassium acetate.

A compound of Formula D for use in Scheme C is a compound wherein T₂ ishalo or another leaving group, and M is as defined above in Scheme B.The compound of Formula B′ may further be converted to a compound ofFormula B″ by treatment with an acid such as hydrochloric acid.

In one embodiment of a compound of Formula B, B′, B″, or E, the G groupsare hydrogen. In another of a compound of Formula B, B′, B″, or E, the Ggroups are R_(G1).

In some embodiments, no further synthetic transformation of M₁ moiety isperformed after the coupling reaction when, e.g. M₁ is2-N-acetyl-benzoxazol-5-yl.

Some exemplary compounds of Formula B that can be synthesized via SchemeC include but are not limited to compounds of the following formulae:

In other embodiments of the invention, a compound of Formula E issynthesized from a compound of Formula F, as shown in Scheme C-1:

Scheme C-1 depicts an exemplary scheme for synthesizing a compound ofFormula E. This reaction proceeds via reacting a compound of Formula Fwith a trialkyl borate or a boronic acid derivative to produce acompound of Formula E. The conditions of the reaction are as describedabove in Scheme C.

A compound of Formula F for use in Scheme C-1 is a compound wherein T₂is halo (including Br, Cl, and I) or another leaving group (includingbut not limited to triflate, tosylate, and mesylate), and the G_(p)moiety is H, acyl, or an amino protecting group including but notlimited to tert-butyl carbamate (Boc), carbobenzyloxy (Cbz), benzyl(Bz), fluorenylmethyloxycarbonyl (FMOC), p-methoxybenzyl (PMB), and thelike.

The compound of Formula E, wherein G is alkyl, may further be convertedto a compound of Formula E, wherein G is hydrogen, by treatment with anacid such as hydrochloric acid

Where desired, deprotection of a substituent (e.g., removal of Bocprotection from an amino substituent) on the benzoxazolyl moiety (i.e.M₁ of Formula C) is performed after coupling the compound of Formula Bto the compound of Formula A.

Some exemplary compounds with such protecting groups, include but arenot limited to compounds of the following formulae:

An exemplary transformation of M₂ to M₁ can be carried out via Scheme Das shown below.

In Step 1, a compound of Formula 3-1 is reacted with boronic acid 3-2,in the presence of palladium tetrakis (triphenylphosphine) and asuitable base, such as sodium carbonate in an aqueous/organic solventmixture to produce a compound of Formula 3-3. In Step 2, the compound ofFormula 3-3 is reacted with about 2 equivalents of nitric acid in aceticacid as solvent to produce a compound of Formula 3-4. Two alternativetransformations may be used to effect the next transformation of Step 3.In the first method, the compound of Formula 3-4 is treated with sodiumdithionite and sodium hydroxide in water to produce a compound ofFormula 3-5. Alternatively, the compound of Formula 3-4 is reduced usingpalladium on carbon in a suitable solvent under a hydrogen atmosphere toyield a compound of Formula 3-5.

In Step 4, compound 3-5 is reacted with about 1.2 equivalents ofcyanogen bromide in a solvent such as methanol/tetrahydrofuran mixtureto produce a compound of Formula 3-6. The compound of Formula 3-6 may befurther transformed by other substitution or derivatization.

A compound of Formula 3-1 useful in the method of Scheme D is a compoundhaving a structure of Formula 3-1, wherein T₁ is triflate or halo(including bromo, chloro, and iodo), and wherein R₁, X₁, X₂, X₃, R₃₁ andR₃₂ are defined as for a compound of Formula I′-A′.

Exemplary compounds having a pyrazolopyrimidine core can be synthesizedvia Scheme E.

In Step 1 of Scheme E, compound A-2 in dimethylformamide (DMF), isreacted with an N— halosuccinimide (NT₁S) at about 80° C., to providecompound 4-1, where T₁ is iodo or bromo. In Step 2, compound 4-1 in DMFis reacted with a a compound R₁T_(x), in the presence of potassiumcarbonate, to provide compound 4-2. In Step 4, compound 4-2 is coupledwith a compound of Formula B using palladium catalysis such as palladiumtetrakis (triphenylphosphine), and in the presence of sodium carbonate,to yield a pyrazolopyrimidine compound as shown.

A compound of Formula R₁T_(x) suitable for use in Reaction Scheme E isthe compound wherein R₁ is cycloalkyl or alkyl and T_(x) is halo(including bromo, iodo, or chloro) or a leaving group, including but notlimited to mesylate or tosylate.

Reaction Schemes F-M illustrate methods of synthesis of borane reagentsuseful in preparing intermediates of use in synthesis of the compoundsof the invention as described in Reaction Schemes A, B, and E above, tointroduce M₁ substituents.

In an alternative method of synthesis, a compound of Formula N-1 and acompound of N-2 are coupled to produce a compound of Formula C. Thecoupling step is typically catalyzed by using, e.g., a palladiumcatalyst, including but not limited to palladium tetrakis(triphenylphosphine). The coupling is generally performed in thepresence of a suitable base, a nonlimiting example being sodiumcarbonate. One example of a suitable solvent for the reaction is aqueousdioxane.

A compound of Formula N-1 for use in Scheme N has a structure of FormulaN-1, wherein G is hydrogen or R_(G1), wherein R_(G1) is alkyl, alkenyl,or aryl. Alternatively, B(OG)₂ of the compound of Formula N-1 is takentogether to form a 5- or 6-membered cyclic moiety. R₁, X₁, X₂, X₃, R₃₁and R₃₂ of the compound of Formula N-1 are defined as for a compound ofFormula I′-A′.

A compound of Formula N-2 for use in Scheme N has a structure of FormulaN-2 wherein T₁ is triflate or halo (including bromo, chloro, and iodo).M of the compound of Formula N-2 is either M₁ or M₂. M₁ is defined asfor a compound of Formula I. For example, M₁ can be a 5-benzoxazolyl ora 6-benzoxazolyl moiety, including but not limited to those M₁ moietiesdisclosed herein. M₂ is a moiety which is synthetically transformed toform M₁, after the M₂ moiety has been coupled to the bicyclic core ofthe compound of Formula N-1.

A compound of Formula N-1 may be synthesized as shown in Scheme N-1. Acompound of Formula N-1 is reacted with a trialkyl borate or a boronicacid derivative to produce a compound of Formula N-1. The reaction istypically run a solvent such as dioxane or tetrahydrofuran. The trialkylborate includes but is not limited to triisopropyl borate and theboronic acid derivative includes but is not limited tobis(pinacolato)diboron.

When the reaction is performed with trialkyl borate, a base such asn-butyllithium is first added to the compound of Formula N-3 to generatean anion, prior to the addition of the borate. When the reaction isperformed with a boronic acid derivative such as bis(pinacolato)diboron,a palladium catalyst and a base is used. Typical palladium catalystsinclude but is not limited to palladium chloride(diphenylphosphino)ferrocene). A suitable base includes but is notlimited to potassium acetate.

A compound of Formula N-3 suitable for use in Scheme N-1 is a compoundwherein T₂ is halo or another leaving group such as mesylate, tosylate,or triflate. X₁, X₂, X₃, R₁, R₃₁, and R₃₂ of the compound of Formula N-3is as defined for a compound of Formula Formula I′-A′.

In some embodiments of the invention, a compound of Formula A, B, B′,B″, C, C″, D, E, E″, 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, N-1″, N-3″, 3-1″,3-3″, 3-4″, 3-5″, 3-6″, N-1″, or N-3″ is provided as its salt, includingbut not limited to hydrochloride, acetate, formate, nitrate, sulfate,and boronate.

In some embodiments of the invention, a palladium compound, includingbut not limited to palladium chloride (diphenylphosphino)ferrocene) andpalladium tetrakis (triphenylphosphine), is used in the synthesis of acompound of Formula A, B, B′, B″, C, C″, D, E, E″, 3-1, 3-2, 3-3, 3-4,3-5, 3-6, N-1″, N-3″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1″, or N-3″ When apalladium compound is present in the synthesis of a compound of FormulaA, B, B′, B″, C, C″, D, E, E″, 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, N-1″, N-3″,3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1″, or N-3″, it is present in an amountranging from about 0.005 molar equivalents to about 0.5 molarequivalents, from about 0.05 molar equivalents to about 0.25 molarequivalents, from about 0.07 molar equivalents to about 0.15 molarequivalents, or about 0.8 molar equivalents to about 0.1 molarequivalents of the compound of Formula A, B, B′, B″, C, D, E, 3-1, 3-2,3-3, 3-4, 3-5, 3-6, N-1, or N-3. In some embodiments, a a palladiumcompound, including but not limited to palladium chloride(diphenylphosphino)ferrocene) and palladium tetrakis(triphenylphosphine) is present in the synthesis of a compound ofFormula A, B, B′, B″, C, C″, D, E, E″, 3-1, 3-2, 3-3, 3-4, 3-5, 3-6,N-1″, N-3″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1″, or N-3″ in about 0.07,about 0.08, about 0.09, about 0.10, about 0.11, about 0.12, about 0.13,about 0.14, or about 0.15 molar equivalents of a starting material ofFormula A, B, B′, B″, C, C″, D, E, E″, 3-1, 3-2, 3-3, 3-4, 3-5, 3-6,N-1″, N-3″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1″, or N-3″ that is used tosynthesize a compound of Formula A, B, B′, B″, C, C″, D, E, E″, 3-1,3-2, 3-3, 3-4, 3-5, 3-6, N-1″, N-3″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, N-1″,or N-3″.

In some embodiments of the above reaction schemes B, D, E, N or N-1,another embodiment of the compounds of Formula A, C, 3-1, 3-3, 3-4, 3-5,3-6, A-2,4-1, 4-2, N-1 and N-3 is as shown in Schemes B′. D′. E′, N′ orN-1′ below. In these alternative syntheses, producing a compound ofFormula C, 3-1, 3-3, 3-4, 3-5, 3-6, A-2,4-1, 4-2, N-1 or N-3, usecompounds that comprise an amino moiety having a R_(G2) moiety presentduring one or more of the synthetic steps, wherein R_(G2) is an aminoprotecting group including but not limited to tert-butyl carbamate(Boc), carbobenzyloxy (Cbz), benzyl (Bz), fluorenylmethyloxycarbonyl(FMOC), p-methoxybenzyl (PMB), and the like. These compounds include acompound of Formula A″, C″, 3-1″, 3-3″, 3-4″, 3-5″, 3-6″, A-2″, 4-1″,4-2″, N-1″ or N-3″.

The R_(G2) moiety is removed, using suitable methods, at any pointdesired, whereupon the compound of Formula C, 3-1, 3-3, 3-4, 3-5, 3-6,A-2,4-1, 4-2, N-1 or N-3 has a R₃₁ hydrogen replacing the R_(G2) moietyon the amino moiety. This transformation is specifically illustrated forthe conversion of a compound of Formula C″ to a compound of C (i.e., asin Step 4 of Scheme E′) and for the conversion of a compound of Formula3-6″ to a compound of Formula 3-6 (ie., as in Step 5 of Scheme D′). Thisillustration is in no way limiting as to the choice of steps wherein acompound comprising a NR₃₁RG₂ moiety may be converted to a compoundcomprising a NR₃₁R₃₂ moiety wherein the R₃₂ moiety is hydrogen.

Additionally, the invention encompasses methods of synthesis of thecompounds of A, B, B′, B″, C, E, 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, N-1 orN-3, wherein one or more of M, M₁, or R₁ has a protecting group presentduring one or more steps of the synthesis. Protecting groups suitablefor use for a M, M₁, or R₁ moiety are well known in the art, as well asthe methods of incorporation and removal, and the reagents suitable forsuch transformations.

Compounds of the invention where X₄ is C—R⁹ may be prepared by methodsanalogous to the ones described in the Schemes illustrated above.

C. Illustrative Subclasses of Compounds of the Invention

Some illustrative compounds of the invention are described below. Thecompounds of the invention are not limited in any way to the compoundsillustrated herein.

Illustrative compounds of the invention include those of subclass 1a,1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b, 8a, 8b, 9a, 9b, 10a,10b, 11a, 11b, 12a, 12b, 13a, 13b, 14a, 14b, 15a, 15b, 16a, or 16b,where the substituents R₁, X₁, and V are as described below.

In some embodiments, when R₁ is H and X₁ is CH, V is phenylamino,benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr,NHCOOMe, CONHMe, or NHSO₂Me. In other embodiments, when R₁ is H and X₁is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH, NHCOMe,NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In other embodiments, whenR₁ is CH₃ and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂,NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. Inother embodiments, when R₁ is CH₃ and X₁ is N, V is phenylamino, benzyl,phenyl, NHMe, NH₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe,CONHMe, or NHSO₂Me. In other embodiments, when R₁ is Et and X₁ is CH, Vis phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH, NHCOMe, NHCOEt,NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In other embodiments, when R₁ isEt and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt,NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is iPr and X₁ is CH, V is phenylamino, benzyl,phenyl, NHMe, NH₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe,CONHMe, or NHSO₂Me. In other embodiments, when R₁ is iPr and X₁ is N, Vis phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH, NHCOMe, NHCOEt,NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In one embodiment, R₁ is iPr, X₁is N, and V is NH₂. In another embodiment, R₁ is iPr, X₁ is N, and V isNHCOMe. In other embodiments, when R₁ is cyclobutyl and X₁ is CH, V isphenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH, NHCOMe, NHCOEt,NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In other embodiments, when R₁ iscyclobutyl and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂,NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. Inother embodiments, when R₁ is cyclopentyl and X₁ is CH, V isphenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH, NHCOMe, NHCOEt,NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In other embodiments, when R₁ iscyclopentyl and X₁ is N V is phenylamino, benzyl, phenyl, NHMe, NH₂,NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. Inother embodiments, when R₁ is phenyl and X₁ is CH, V is phenylamino,benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr,NHCOOMe, CONHMe, or NHSO₂Me. In other embodiments, when R₁ is phenyl andX₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is pyridin-2-yl and X₁ is CH, V is phenylamino,benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr,NHCOOMe, CONHMe, or NHSO₂Me. In other embodiments, when R₁ ispyridin-2-yl and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂,NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. Inother embodiments, when R₁ is N-methylaminocyclohex-4-yl and X₁ is CH, Vis phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH, NHCOMe, NHCOEt,NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In other embodiments, when R₁ isN-methylaminocyclohex-4-yl and X₁ is N, V is phenylamino, benzyl,phenyl, NHMe, NH₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe,CONHMe, or NHSO₂Me. In other embodiments, when R₁ isN-methylpiperidin-4-yl and X₁ is CH, V is phenylamino, benzyl, phenyl,NHMe, NH₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, orNHSO₂Me. In other embodiments, when R₁ is N-methylpiperidin-4-yl and X₁is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH, NHCOMe,NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In other embodiments, whenR₁ is N-methylaminocyclobut-3-yl and X₁ is CH, V is phenylamino, benzyl,phenyl, NHMe, NH₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe,CONHMe, or NHSO₂Me. In other embodiments, when R₁ isN-methylaminocyclobut-3-yl and X₁ is N, V is phenylamino, benzyl,phenyl, NHMe, NH₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe,CONHMe, or NHSO₂Me. In other embodiments, when R₁ is tert-butyl and X₁is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH, NHCOMe,NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In other embodiments, whenR₁ is tert-butyl and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe,NH₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me.In other embodiments, when R₁ is 1-cyano-but-4-yl and X₁ is CH, V isphenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH, NHCOMe, NHCOEt,NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In other embodiments, when R₁ is1-cyano-but-4-yl and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe,NH₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me.In other embodiments, when R₁ is 1-cyano-prop-3-yl and X₁ is CH, V isphenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH, NHCOMe, NHCOEt,NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In other embodiments, when R₁ is1-cyano-prop-3-yl and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe,NH₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me.In other embodiments, when R₁ is 3-azetidinyl and X₁ is CH, V isphenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH, NHCOMe, NHCOEt,NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In other embodiments, when R₁ is3-azetidinyl and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, —NH₂,NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me.

In other embodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, —NH₂, NHEt NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

NH and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt,NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOHNHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

NH₂ and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt,NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ s , V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOHNHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, —NH₂, NHEt NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, —NH₂, NHEt NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, —NH₂, NHEt NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOHNHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, —NH₂, NHEt NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me.

In other embodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, —NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. and X₁ is CH, V isphenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH, NHCOMe, NHCOEt,NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me.

In other embodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, —NH₂, NHEt NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, —NH₂, NHEt NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

C and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, —NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, —NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is CH, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me. In otherembodiments, when R₁ is

and X₁ is N, V is phenylamino, benzyl, phenyl, NHMe, NH₂, NHEt, NHCOH,NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO₂Me.

In the noted embodiments, pyridin-2-yl is ,

N-methylaminocyclohex-4-yl is

N-methylpiperidin-4-yl is

and N-methylaminocyclobut-3-yl is

Illustrative compounds of the invention include those of subclass 1a,1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b, 8a, 8b, 9a, 9b, 10a,10b, 11a, 11b, 12a, 12b, 13a, 13b, 14a, 14b, 15a, 15b, 16a, or 16b,where the substituents R₁, X₁, and V are as described below. In someembodiments, when R₁ is H and X₁ is CH, V is cyclopropanecarboxamido,cyclopropylamino, morpholinoethylamino, hydroxyethylamino, orN-morpholino. In other embodiments, when R₁ is H and X₁ is N, V iscyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,hydroxyethylamino, or N-morpholino. In some embodiments, when R₁ is CH₃and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is CH₃ and X₁ is N, V is cyclopropanecarboxamido,cyclopropylamino, morpholinoethylamino, hydroxyethylamino, orN-morpholino. In some embodiments, when R₁ is Et and X₁ is CH, V iscyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,hydroxyethylamino, or N-morpholino. In other embodiments, when R₁ is Etand X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In someembodiments, when R₁ is iPr and X₁ is CH, V is cyclopropanecarboxamido,cyclopropylamino, morpholinoethylamino, hydroxyethylamino, orN-morpholino. In other embodiments, when R₁ is iPr and X₁ is N, V iscyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,hydroxyethylamino, or N-morpholino. In some embodiments, when R₁ iscyclobutyl and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is cyclobutyl and X₁ is N, V iscyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,hydroxyethylamino, or N-morpholino. In some embodiments, when R₁ iscyclopentyl and X₁ is CH, V is cyclopropanecarboxamido,cyclopropylamino, morpholinoethylamino, hydroxyethylamino, orN-morpholino. In other embodiments, when R₁ is cyclopentyl and X₁ is N,V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,hydroxyethylamino, or N-morpholino. In some embodiments, when R₁ isphenyl and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is phenyl and X₁ is N, V iscyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,hydroxyethylamino, or N-morpholino. In some embodiments, when R₁ ispyridin-2-yl and X₁ is CH, V is cyclopropanecarboxamido,cyclopropylamino, morpholinoethylamino, hydroxyethylamino, orN-morpholino. In other embodiments, when R₁ is pyridin-2-yl and X₁ is N,V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,hydroxyethylamino, or N-morpholino. In some embodiments, when R₁ isN-methylaminocyclohex-4-yl and X₁ is CH, V is cyclopropanecarboxamido,cyclopropylamino, morpholinoethylamino, hydroxyethylamino, orN-morpholino. In other embodiments, when R₁ isN-methylaminocyclohex-4-yl and X₁ is N, V is cyclopropanecarboxamido,cyclopropylamino, morpholinoethylamino, hydroxyethylamino, orN-morpholino. In some embodiments, when R₁ is N-methylpiperidin-4-yl andX₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is N-methylpiperidin-4-yl and X₁ is N, V iscyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,hydroxyethylamino, or N-morpholino. In some embodiments, when R₁ isN-methylaminocyclobut-3-yl and X₁ is CH, V is cyclopropanecarboxamido,cyclopropylamino, morpholinoethylamino, hydroxyethylamino, orN-morpholino. In other embodiments, when R₁ isN-methylaminocyclobut-3-yl and X₁ is N, V is cyclopropanecarboxamido,cyclopropylamino, morpholinoethylamino, hydroxyethylamino, orN-morpholino. In other embodiments, when R₁ is tert-butyl and X₁ is CH,V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,hydroxyethylamino, or N-morpholino. In other embodiments, when R₁ istert-butyl and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is 1-cyano-but-4-yl and X₁ is CH, V iscyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,hydroxyethylamino, or N-morpholino. In other embodiments, when R₁ is1-cyano-but-4-yl and X₁ is N, V is cyclopropanecarboxamido,cyclopropylamino, morpholinoethylamino, hydroxyethylamino, orN-morpholino. In other embodiments, when R₁ is 1-cyano-prop-3-yl and X₁is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is 1-cyano-prop-3-yl and X₁ is N, V iscyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,hydroxyethylamino, or N-morpholino. In other embodiments, when R₁ is3-azetidinyl and X₁ is CH, V is cyclopropanecarboxamido,cyclopropylamino, morpholinoethylamino, hydroxyethylamino, orN-morpholino. In other embodiments, when R₁ is 3-azetidinyl and X₁ is N,V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,hydroxyethylamino, or N-morpholino. In other embodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino.

In other embodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. and X₁ is CH,V is cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,hydroxyethylamino, or N-morpholino.

In other embodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is CH, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino. In otherembodiments, when R₁ is

and X₁ is N, V is cyclopropanecarboxamido, cyclopropylamino,morpholinoethylamino, hydroxyethylamino, or N-morpholino.

In the noted embodiments, cyclopropanecarboxamido is

cyclopropylamino is

2-morpholinoethylamino is

hydroxyethylamino is

and N-morpholino is

TABLE 1 Biological activity of several illustrative compounds of theinvention. mTOR PI3K α PI3K β PI3K γ PI3K δ PC3 Structure IC₅₀ (nM) IC₅₀(nM) IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) EC50 (nM) 1

++++ +++ ++ ++++ +++ ++++ 2

++++ ++ + +++ +++ +++ 3

++ + ++ ++ ++ 4

+++ ++ ++ +++ +++ ++ 5

++++ +++ ++ ++++ +++ ++++ 6

++++ ++ + ++ +++ +++ 7

++++ +++ ++ ++ +++ ++ 8

++++ +++ + +++ +++ ++++ 9

++++ ++ + +++ +++ ++++ 10

++ + 11

+++ + 12

+++ + 13

++ ++ +++ +++ 14

++ ++ +++ ++ 15

+ + + + 16

+ + ++ + 17

+ + + + 18

+ + + + 19

++ + + + 20

++ ++ + ++ 21

+++ + + + + 22

++++ ++++ ++ +++ +++ ++ 23

++++ ++ + ++ ++ 24

+ + + + 25

+++ ++ ++++ +++ 26

++++ +++ ++++ +++ 27

++ + + +++ Table 1 shows the biological activity in mTOR and PI3K kinaseassays of several compounds of the invention. The scale utilized inTable 1 is as follows: ++++ less than 100 nM; +++ less than 1.0 μM; ++less than 10 μM; and + greater than 10 μM.

In other embodiments, the present invention provides the followingcompounds:

Any of the compounds shown above may show a biological activity in anmTOR or PI3K inhibition assay of between about 0.5 nM and 25 μM (IC₅₀).

In some embodiments, one or more compounds of the invention may bindspecifically to a PI3 kinase or a protein kinase selected from the groupconsisting of mTor, DNA-dependent protein kinase DNA-dependent proteinkinase (Pubmed protein accession number (PPAN) AAA79184), Abl tyrosinekinase (CAA52387), Bcr-Abl, hemopoietic cell kinase (PPAN CAI19695), Src(PPAN CAA24495), vascular endothelial growth factor receptor 2 (PPANABB82619), vascular endothelial growth factor receptor-2 (PPANABB82619), epidermal growth factor receptor (PPAN AG43241), EPH receptorB4 (PPAN EAL23820), stem cell factor receptor (PPAN AAF22141),Tyrosine-protein kinase receptor TIE-2 (PPAN Q02858), fms-relatedtyrosine kinase 3 (PPAN NP_(—)004110), platelet-derived growth factorreceptor alpha (PPAN NP_(—)990080), RET (PPAN CAA73131), and any otherprotein kinases listed in the appended tables and figures, as well asany functional mutants thereof. In some embodiments, the IC50 of acompound of the invention for p110α, p110β, p110γ, or p110δ is less thanabout 1 uM, less than about 100 nM, less than about 50 nM, less thanabout 10 nM, less than 1 nM or even less than about 0.5 nM. In someembodiments, the IC50 of a compound of the invention for mTor is lessthan about 1 uM, less than about 100 nM, less than about 50 nM, lessthan about 10 nM, less than 1 nM or even less than about 0.5 nM. In someother embodiments, one or more compounds of the invention exhibit dualbinding specificity and are capable of inhibiting a PI3 kinase (e.g., aclass I PI3 kinase) as well as a protein kinase (e.g., mTor) with anIC50 value less than about 1 uM, less than about 100 nM, less than about50 nM, less than about 10 nM, less than 1 nM or even less than about 0.5nM. In some embodiments, one or more compounds of the invention may becapable of inhibiting tyrosine kinases including, for example,DNA-dependent protein kinase DNA-dependent protein kinase (Pubmedprotein accession number (PPAN) AAA79184), Abl tyrosine kinase(CAA52387), Bcr-Abl, hemopoietic cell kinase (PPAN CAI19695), Src (PPANCAA24495), vascular endothelial growth factor receptor 2 (PPANABB82619), vascular endothelial growth factor receptor-2 (PPANABB82619), epidermal growth factor receptor (PPAN AG43241), EPH receptorB4 (PPAN EAL23820), stem cell factor receptor (PPAN AAF22141),Tyrosine-protein kinase receptor TIE-2 (PPAN Q02858), fms-relatedtyrosine kinase 3 (PPAN NP_(—)004110), platelet-derived growth factorreceptor alpha (PPAN NP_(—)990080), RET (PPAN CAA73131), and functionalmutants thereof. In some embodiments, the tyrosine kinase is Abl,Bcr-Abl, EGFR, or Flt-3, and any other kinases listed in the Tablesherein.

In some embodiments, one or more compounds of the invention yieldselective inhibition of mTor-mediated signal transduction as compared toupstream PI3K. In some other embodiments, the compounds provided hereincan inhibit mTor-mediated activity more effectively than rapamycin,hence providing an alternative treatment for rapamycin-resistantconditions.

In some embodiments, the compounds of the invention including but notlimited to those shown in Table 1 selectively inhibit both mTorC1 andmTorC2 activity relative to one, two, three or all type Iphosphatidylinositol 3-kinases (PI3-kinase). As noted above type IPI3-kinases are PI3-kinase α, PI3-kinase f, PI3-kinase γ, and PI3-kinaseδ. For instance, one or more compounds of the invention may inhibitmTORC1 and mTORC2 with an IC50 that is 1/10^(th), 1/20^(th), 1/25^(th),1/50^(th), 1/100^(th), 1/200^(th), 1/300^(th), 1/400^(th), 1/500^(th),1/1000^(th), 1/2000^(th) or less than the IC50 for one or more type IPI3-kinases consisting of PI3-kinase α, PI3-kinase β, PI3-kinase γ, andPI3-kinase δ. In some embodiments, one or more compounds of theinvention are substantially ineffective in inhibiting a type IPI3-kinase at a concentration of 100 nM, 200 nM, 500 nM, or 1 uM, 5 uMor 10 uM, or higher in an in vitro kinase assay.

In other embodiments, the compounds of the invention including but notlimited to compound I and others shown in Table 1 selectively inhibitboth mTORC1 and mTORC2 activity relative to one, two, three or all typeII or III PI3-kinases, for example, PI3KC2α, PI3KC2β, and VPS34. Inparticular, one or more of the compounds of the invention may inhibitmTORC1 and mTORC2 with an IC₅₀ that is 1/10^(th), 1/20^(th), 1/25^(th),1/50^(th), 1/100^(th), 1/200^(th), 1/300^(th), 1/400^(th), 1/500^(th),1/1000^(th), 1/2000^(th) or less than the IC₅₀ for one or more type IIor III PI3-kinases.

In yet another embodiment, compounds of the invention including but notlimited to compound I and others shown in Table 1 selectively inhibitboth mTORC1 and mTORC2 activity relative to one or more PI4-kinases suchas PI4Kα and PI4Kβ. For instance, one or more compounds of the inventionmay inhibit mTORC1 and mTORC2 with an IC₅₀ that is 1/10^(th), 1/20^(th),1/25^(th), 1/50^(th), 1/100^(th), 1/200^(th), 1/300^(th), 1/400^(th),1/500^(th), 1/1000^(th), 1/2000^(th) or less than the IC₅₀ for one ormore PI4-kinases.

In still another embodiment, the compounds of the invention includingbut not limited to those shown in Table 1 selectively inhibit bothmTORC1 and mTORC2 activity relative to one or more protein kinasesincluding serine/threonine kinase such as DNA-PK. Such selectiveinhibition can be evidenced by, e.g., the IC₅₀ value of the compound ofthe invention that can be ½, ⅓^(rd), ¼^(th), ⅕^(th), 1/7^(th),1/10^(th), 1/15^(th), 1/20^(th), 1/25^(th), 1/30^(th), 1/40^(th),1/50^(th), 1/100^(th), 1/150^(th), 1/200^(th), 1/300^(th), 1/400^(th),1/500^(th), 1/1000^(th), 1/2000^(th) or less as compared to that of areference protein kinase. In some instances, the compounds of theinvention including but not limited to those shown in Table 1 lacksubstantial cross-reactivity with at least about 100, 200, 300, or moreprotein kinases other than mTORC1 or mTORC2. The lack of substantialcross-reactivity with other non-mTor protein kinases can be evidencedby, e.g., at least 50%, 60%, 70%, 80%, 90% or higher kinase activityretained when the compound of the invention is applied to the proteinkinase at a concentration of 1 μM, 5 μM, 10 μM or higher.

In some embodiments, one or more compounds of the invention selectivelyinhibits both mTor activity with an IC50 value of about 100 nM, 50 nM,10 nM, 5 nM, 100 pM, 10 pM or even 1 pM, or less as ascertained in an invitro kinase assay.

In some embodiments, one or more compounds of the invention inhibitsphosphorylation of Akt (S473) and Akt (T308) more effectively thanrapamycin when tested at a comparable molar concentration in an in vitrokinase assay.

In some embodiments, one or more compounds of the invention competeswith ATP for binding to ATP-binding site on mTorC1 and/or mTorC2.

In some embodiments, one or more compounds of the invention are capableof inhibiting and/or otherwise modulating cellular signal transductionvia one or more protein kinases or lipid kinases disclosed herein. Forexample, one or more compounds of the invention are capable ofinhibiting or modulating the output of a signal transduction pathway.Output of signaling transduction of a given pathway can be measured bythe level of phosphorylation, dephosphorylation, fragmentation,reduction, oxidation of a signaling molecule in the pathway of interest.In another specific embodiment, the output of the pathway may be acellular or phenotypic output (e.g. modulating/inhibition of cellularproliferation, cell death, apoptosis, autophagy, phagocytocis, cellcycle progression, metastases, cell invasion, angiogenesis,vascularization, ubiquitination, translation, transcription, proteintrafficking, mitochondrial function, golgi function, enodplasmicreticular function, etc). In some embodiments, one or more compounds ofthe invention are capable of, by way of example, causing apoptosis,causing cell cycle arrest, inhibiting cellular proliferation, inhibitingtumor growth, inhibiting angiogenesis, inhibiting vascularization,inhibiting metastases, and/or inhibiting cell invasion.

In some embodiments, one or more compounds of the invention causesapoptosis of said cell or cell cycle arrest. Cell cycle can be arrestedat the G0/G1 phase, S phase, and/or G2/M phase by the subject compounds.

In some embodiments, one or more compounds of the invention includingbut not limited to the compounds listed in Table 1 are capable ofinhibiting cellular proliferation. For example, in some cases, one ormore compounds of the invention listed in Table 1 may inhibitproliferation of tumor cells or tumor cell lines with a wide range ofgenetic makeup. In some cases, the compounds of the invention mayinhibit PC3 cell proliferation in vitro or in an in vivo model such as axenograft mouse model. In some cases, in vitro cultured PC3 cellproliferation may be inhibited with an IC50 of less than 100 nM, 75 nM,50 nM, 25 nM, 15 nM, 10 nM, 5 nM, 3 nM, 2 nM, 1 nM, 0.5 nM, 0.1 nM orless by one or more compounds of the invention listed in Table 1.

In some cases, phosphorylation of AKT may be inhibited with an IC50 ofless than 100 nM, 75 nM, 50 nM, 25 nM, 15 nM, 10 nM, 5 nM, 3 nM, 2 nM, 1nM, 0.5 nM, 0.1 nM or less by one or more compounds of the inventionlisted in Table 1. Inhibition of phosphorylation of AKT may be apartially or completely blocked by the addition of human whole blood. Insome cases, the one or more compounds of the invention listed in Table 1exhibit specific binding and/or inhibition of mTOR as evidenced by asmall (e.g. less than about 0.5-fold, 1-fold, 2-fold, or 3-fold)increase in IC50 for inhibition of AKT phosphorylation of cells culturedin whole blood as compared to standard culture media (e.g. DMEM 10%FBS).

In some cases, proliferation of primary tumors derived from subjects(e.g. cancer patients) can be inhibited by a compound of the inventionas shown by in vitro assays, or in vivo models (e.g. using the subjects'tumor cells for generating a xenograft mode). In some cases primarytumor cell line proliferation may be inhibited with an IC50 of less than100 nM, 75 nM, 50 nM, 25 nM, 15 nM, 10 nM, 5 nM, 3 nM, 2 nM, 1 nM, 0.5nM, 0.1 nM or even less by one or more compounds of the invention listedin Table 1. In some cases, the average IC50 of a compound of theinvention for inhibiting a panel 10, 20, 30, 40, 50, 100 or more primarytumor cells may be about 200 nM, 100 nM, 75 nM, 50 nM, 25 nM, 15 nM, 10nM, 5 nM, 3 nM, 2 nM, 1 nM, 0.5 nM, 0.1 nM or even less. The tumor cellsthat can be inhibited by the compounds of the present invention includebut are not limited to pancreatic, renal (kidney), bone, nasopharyngeal,gastric, stomach, ovarian, oral, breast, blood, prostate, rectal, colon,colorectal, blial, neural, lung, and dermal cells.

In some embodiments, the compounds of the invention are effective inblocking cell proliferation signals in cells deficient in PTEN activitybut expressing PI3Ka. In some cases, cell proliferation signalling maybe inhibited by one or more compounds of the invention including but notlimited to those shown in Table 1 as evidenced by Western blot analysisof phosphorylation of proteins such as AKT (phosphorylation at T308 orS473), 4EBP1 (phosphorylation at S65), S6 (phosphorylation at S240/244),FOXO1 (phosphorylation at T24/3a T32), GSK3(3 (phosphorylation at S9),PRAS40 (phosphorylation at T246), or MAPK phosphorylation. In somecases, the compounds of the invention can inhibit phosphorylation of anyone of these targets to a greater degree than rapamycin under theconditions tested. In other cases, the compounds of the invention caninhibit phosphorylation of signaling proteins and suppress proliferationof cells containing these signaling proteins but are resistant toexisting chemotherapeutic agents including but not limited to rapamycin,Gleevec, dasatinib, alkylating agents, antimetabolites, anthracyclines,plant alkaloids, topoisomerase inhibitors and other antitumor agentsdisclosed herein.

In some embodiments, the compounds of the invention including but notlimited to those shown in Table 1, may inhibit tumor cells comprising awide range of activating or tumor-causing mutations. Such mutationsinclude but are not limited to mutations in KRAS, PI3KCα, BRAF, TSC1/2,PBKclass A, LAT1, and PTEN. For example, one or more compounds of theinvention such as the compounds in Table 1, including but not limited tocompound I may inhibit proliferation of tumor cells comprising mutationsin KRAS at G12, G13, or mutations in Q61 including but not limited tothe G12V, G12S, G13D, Q61K, and Q61H mutations. In another example, oneor more compounds of the invention may inhibit proliferation of tumorcells comprising mutations in BRAF at V600 including but not limited tothe mutation V600E. In another example, one or more compounds of theinvention such as the compounds in Table 1 may inhibit proliferation oftumor cells comprising a mutation in PI3KCα at E545, P449, or H1047including but not limited to the E545K, H1047R, and P449T mutations. Inyet another example, one or more compounds of the invention such as thecompounds in Table 1, may inhibit proliferation of tumor cellscomprising activating mutations in one or more combinations of genessuch as for example activating mutations in PTEN and KRAS, PTEN andBRAF, or PTEN and PI3KCα. In yet another example, one or more compoundsof the invention such as the compounds in Table 1 may inhibit tumorcells or tumor cell lines comprising activating mutations in one or morecombinations of genes such as for example activating mutations in BRAFand PI3KCα.

In some embodiments, one or more compounds of the invention includingthose in Table 1 may cause cell cycle arrest. In some cases, cellstreated with one or more compounds of the invention including compound Iand others in Table 1, may arrest or take longer to proceed through oneor more cell cycle stages such as G₀/G₁, S, or G₂/M. For example, cellstreated with one or more compounds of the invention may arrest or takelonger to proceed through the G₀/G₁ cell cycle stage. In some cases,about 35%, 40%, 50%, 55%, 60%, 65%, 70% or more of cells treated withone or more compounds of the invention may be in the G₀/G₁ cell cyclestage. In some cases, cells exhibiting cell cycle arrest in the G₀/G₁cell cycle stage in response to treatment with the compounds of theinvention are tumor cells or rapidly dividing cells. In some cases,cells exhibiting cell cycle arrest in the G₀/G₁ cell cycle stage inresponse to treatment with one or more compounds of the presentinvention are HCT116 cells or SW620 cells. In some cases, one or morecompounds of the invention such as the compounds in Table 1, includingbut not limited to compound I exhibit a comparable or a greater degreeof G₀/G₁ arrest as compared to an inhibitor that inhibits one or morePI3-kinases. In some cases, the compounds of the invention effect acomparable or a greater degree of G₀/G₁ arrest as compared to aninhibitor that inhibits both mTOR and one or more PI3Ks in tumor cells.In some cases, the compounds of the invention effect a comparable or agreater degree of G₀/G₁ arrest as compared to rapamycin or doxorubicin.

In some embodiments, cell signalling in tumor cells xenografted intofemale athymic nude mice may be inhibited by one or more compounds ofthe invention such as the compounds in Table 1, including but notlimited to compound I. In some cases, cell signalling may be inhibitedby one or more compounds of the invention as evidenced by western blotdetection of phosphorylation of proteins extracted from homogenizedtumors, such as AKT phosphorylation at T308 or S473, 4EBP1phosphorylation at S65, S6 phosphorylation at S240/244. In some cases,inhibition of phosphorylation may be comparable to or greater than thatprovided by known inhibitors of phosphorylation such as a Pan PI3Kinhibitor that also inhibits one or more isoforms of mTOR (Pan PI3K/mTorinhibitor) under the conditions tested. In other cases, one or morecompounds of the invention may inhibit phosphorylation of proteins thatother inhibitors such as Pan PI3K/mTor inhibitors do not affect, or havelittle effect on, e.g., phosphorylation of AKT at T308 and S473.

In some embodiments, the compounds of the invention including but notlimited to compound I and others shown in Table 1, cause a reduction intumor volume of xenograft tumors in female nude athymic mice. Forexample, treatment with one or more compounds of the invention resultsin a reduction in the growth or tumor volume caused by engraftment ofU87-MG, A549, ZR-75-1, or 786-0 tumor cells in nude mice. The compoundsof the invention may be administered orally, subcutaneously, orintravenously, or any other compound administration methods providedherein. In some cases, the compounds are administered once a week, everyother day, once a day, twice a day, three times a day, four times a dayor more. In some cases, 0.01 mg/kg of compound is administered, 0.05mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 2mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 7.5 mg/kg, 10 mg/kg, 100 mg/kg or morecompound is administered at a time. In some cases, a significantreduction in tumor volume may be detected within 5, 10, 15, 20, 25, or30 days of tumor engraftment.

The invention provides a pharmaceutical composition comprising one ormore compounds disclosed herein. In some embodiments the inventionprovides pharmaceutical compositions for the treatment of disorders suchas hyperproliferative disorders including but not limited to cancerssuch as acute myeloid leukemia, lymphoma, thymus, brain, lung, squamouscell, skin, eye, retinoblastoma, intraocular melanoma, mesothelioma,mediastinum, oral cavity and oropharyngeal, bladder, gastric, stomach,pancreatic, bladder, breast, cervical, head, neck, renal, kidney, liver,hepatobiliary system, small intestine, colon, rectum, anus, , prostate,colorectal, urethra, esophageal, testicular, gynecological, penis,testis, ovarian, endocrine system, skin, thyroid, CNS, PNS, AIDS relatedAIDS-Related (e.g. Lymphoma and Kaposi's Sarcoma), other viral-inducedcancers, sarcomas of the soft tissue and bone, and melanomas ofcutaneous and intraocular origin. Cancers includes solid tumors as wellas hematological malignancies. In addition, a cancer at any stage ofprogression can be treated, such as primary, metastatic, and recurrentcancers.

In some embodiments, said pharmaceutical composition is for thetreatment of a non-cancerous hyperproliferative disorder such as abenign tumor, for example but not limited to, for the treatment of abenign hyperplasia of the skin (e.g., psoriasis), breast, lung, kidney,pancreas, restenosis, or prostate (e.g., benign prostatic hypertrophy(BPH)).

In some embodiments, the invention provides pharmaceutical compositionsfor treating diseases or conditions related to an undesirable,over-active, harmful or deleterious immune response in a mammal. Suchundesirable immune response can be associated with or result in e.g.asthma, emphysema, bronchitis, psoriasis, allergy, anaphylaxsis,autoimmune diseases, rhuematoid arthritis, graft versus host disease,and lupus erythematosus. The pharmaceutical compositions of the presentinvention can be used to treat other respiratory diseases including butnot limited to disease affecting the lobes of the lung, the pleuralcavity, bronchial tubes, trachea, upper respiratory tract, or the nervesand muscle responsible for breathing.

The invention also provides compositions for the treatment of multiorganfailure.

The invention also provides compositions for the treatment of liverdiseases (including diabetes), pancreatitis, gall bladder disease(including gallstones), or kidney disease (including proliferativeglomerulonephritis and diabetes-induced renal disease) or pain in amammal.

The invention further provides a composition for the prevention ofblastocyte implantation in a mammal.

The invention also relates to a composition for treating a diseaserelated to vasculogenesis or angiogenesis in a mammal, which canmanifest as tumor angiogenesis, chronic inflammatory disease such asrheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skindiseases such as psoriasis, eczema, and scleroderma, diabetes, diabeticretinopathy, retinopathy of prematurity, age-related maculardegeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung, pancreatic, prostate, colon and epidermoidcancer.

The invention further provides compositions for the treatment ofdisorders involving platelet aggregation or platelet adhesion, includingbut not limited to Bernard-Soulier syndrome, Glanzmann's thrombasthenia,Scott's syndrome, von Willebrand disease, Hermansky-Pudlak Syndrome, andGray platelet syndrome.

In some embodiments, compositions are provided for treating a diseasewhich is skeletal muscle atrophy, skeletal or muscle hypertrophy. Theinvention further provides compositions for the treatment of disordersthat include but are not limited to cancers as discussed herein,transplantation-related disorders (e.g., lowering rejection rates,graft-versus-host disease, etc.), muscular sclerosis (MS), allergicdisorders (e.g. arthritis, allergic encephalomyelitis) and otherimmunosuppressive-related disorders, metabolic disorders (e.g.,diabetes), reducing intimal thickening following vascular injury, andmisfolded protein disorders (e.g., Alzheimer's Disease, Gaucher'sDisease, Parkinson's Disease, Huntington's Disease, cystic fibrosis,macular degeneration, retinitis pigmentosa, and prion disorders) (asmTOR inhibition can alleviate the effects of misfolded proteinaggregates). The disorders also include hamartoma syndromes, such astuberous sclerosis and Cowden Disease (also termed Cowden syndrome andmultiple hamartoma syndrome)

In some embodiments, the invention provides a pharmaceutical compositionfor treating ophthalmic disorders. The composition is formulated forocular administration and it contains an effective amount of a compoundof the present invention and a pharmaceutical excipient suitable forocular administration. Pharmaceutical compositions of the inventionsuitable for ocular administration can be presented as discrete dosageforms, such as drops or sprays each containing a predetermined amount ofan active ingredient a solution, or a suspension in an aqueous ornon-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquidemulsion. Eye drops may be prepared by dissolving the active ingredientin a sterile aqueous solution such as physiological saline, bufferingsolution, etc., or by combining powder compositions to be dissolvedbefore use. Other vehicles may be chosen, as is known in the art,including but not limited to: balance salt solution, saline solution,water soluble polyethers such as polyethylene glycol, polyvinyls, suchas polyvinyl alcohol and povidone, cellulose derivatives such asmethylcellulose and hydroxypropyl methylcellulose, petroleum derivativessuch as mineral oil and white petrolatum, animal fats such as lanolin,polymers of acrylic acid such as carboxypolymethylene gel, vegetablefats such as peanut oil and polysaccharides such as dextrans, andglycosaminoglycans such as sodium hyaluronate. If desired, additivesordinarily used in the eye drops can be added. Such additives includeisotonizing agents (e.g., sodium chloride, etc.), buffer agent (e.g.,boric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate,etc.), preservatives (e.g., benzalkonium chloride, benzethoniumchloride, chlorobutanol, etc.), thickeners (e.g., saccharide such aslactose, mannitol, maltose, etc.; e.g., hyaluronic acid or its salt suchas sodium hyaluronate, potassium hyaluronate, etc.; e.g.,mucopolysaccharide such as chondroitin sulfate, etc.; e.g., sodiumpolyacrylate, carboxyvinyl polymer, crosslinked polyacrylate, polyvinylalcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propylmethylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose,hydroxy propyl cellulose or other agents known to those skilled in theart).

The subject pharmaceutical compositions are typically formulated toprovide a therapeutically effective amount of a compound of the presentinvention as the active ingredient, or a pharmaceutically acceptablesalt, ester, prodrug, solvate, hydrate or derivative thereof. Wheredesired, the pharmaceutical compositions contain pharmaceuticallyacceptable salt and/or coordination complex thereof, and one or morepharmaceutically acceptable excipients, carriers, including inert soliddiluents and fillers, diluents, including sterile aqueous solution andvarious organic solvents, permeation enhancers, solubilizers andadjuvants.

The subject pharmaceutical compositions can be administered alone or incombination with one or more other agents, which are also typicallyadministered in the form of pharmaceutical compositions. Where desired,the one or more compounds of the invention and other agent(s) may bemixed into a preparation or both components may be formulated intoseparate preparations to use them in combination separately or at thesame time.

In some embodiments, the concentration of one or more compounds providedin the pharmaceutical compositions of the present invention is less than100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%,14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%,0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%,0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%,0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%,0.0003%, 0.0002%, or 0.0001% w/w, w/v or v/v.

In some embodiments, the concentration of one or more compounds of theinvention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%,17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%,14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%,12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%,9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%,6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%,3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125% ,1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%,0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%,0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%,0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v.

In some embodiments, the concentration of one or more compounds of theinvention is in the range from approximately 0.0001% to approximately50%, approximately 0.001% to approximately 40%, approximately 0.01% toapproximately 30%, approximately 0.02% to approximately 29%,approximately 0.03% to approximately 28%, approximately 0.04% toapproximately 27%, approximately 0.05% to approximately 26%,approximately 0.06% to approximately 25%, approximately 0.07% toapproximately 24%, approximately 0.08% to approximately 23%,approximately 0.09% to approximately 22%, approximately 0.1% toapproximately 21%, approximately 0.2% to approximately 20%,approximately 0.3% to approximately 19%, approximately 0.4% toapproximately 18%, approximately 0.5% to approximately 17%,approximately 0.6% to approximately 16%, approximately 0.7% toapproximately 15%, approximately 0.8% to approximately 14%,approximately 0.9% to approximately 12%, approximately 1% toapproximately 10% w/w, w/v or v/v.

In some embodiments, the concentration of one or more compounds of theinvention is in the range from approximately 0.001% to approximately10%, approximately 0.01% to approximately 5%, approximately 0.02% toapproximately 4.5%, approximately 0.03% to approximately 4%,approximately 0.04% to approximately 3.5%, approximately 0.05% toapproximately 3%, approximately 0.06% to approximately 2.5%,approximately 0.07% to approximately 2%, approximately 0.08% toapproximately 1.5%, approximately 0.09% to approximately 1%,approximately 0.1% to approximately 0.9% w/w, w/v or v/v.

In some embodiments, the amount of one or more compounds of theinvention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g,2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g,0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g,0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g,0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g,0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

In some embodiments, the amount of one or more compounds of theinvention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g,0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g,0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g,0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g,0.095 g, 0.1 g, , 0.15 g, 0.2 g, , 0.25 g, 0.3 g, , 0.35 g, 0.4 g, ,0.45 g, 0.5 g, 0.55 g, 0.6 g, , 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g,0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.

In some embodiments, the amount of one or more compounds of theinvention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

The compounds according to the invention are effective over a widedosage range. For example, in the treatment of adult humans, dosagesfrom 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, andfrom 5 to 40 mg per day are examples of dosages that may be used. Anexemplary dosage is 10 to 30 mg per day. The exact dosage will dependupon the route of administration, the form in which the compound isadministered, the subject to be treated, the body weight of the subjectto be treated, and the preference and experience of the attendingphysician.

A pharmaceutical composition of the invention typically contains anactive ingredient (e.g., a compound) of the present invention or apharmaceutically acceptable salt and/or coordination complex thereof,and one or more pharmaceutically acceptable excipients, carriers,including but not limited to inert solid diluents and fillers, diluents,sterile aqueous solution and various organic solvents, permeationenhancers, solubilizers and adjuvants.

Described below are non-limiting exemplary pharmaceutical compositionsand methods for preparing the same.

Pharmaceutical Compositions for Oral Administration.

In some embodiments, the invention provides a pharmaceutical compositionfor oral administration containing a compound of the invention, and apharmaceutical excipient suitable for oral administration.

In some embodiments, the invention provides a solid pharmaceuticalcomposition for oral administration containing: (i) an effective amountof a compound of the invention; optionally (ii) an effective amount of asecond agent; and (iii) a pharmaceutical excipient suitable for oraladministration. In some embodiments, the composition further contains:(iv) an effective amount of a third agent.

In some embodiments, the pharmaceutical composition may be a liquidpharmaceutical composition suitable for oral consumption. Pharmaceuticalcompositions of the invention suitable for oral administration can bepresented as discrete dosage forms, such as capsules, cachets, ortablets, or liquids or aerosol sprays each containing a predeterminedamount of an active ingredient as a powder or in granules, a solution,or a suspension in an aqueous or non-aqueous liquid, an oil-in-wateremulsion, or a water-in-oil liquid emulsion. Such dosage forms can beprepared by any of the methods of pharmacy, but all methods include thestep of bringing the active ingredient into association with thecarrier, which constitutes one or more necessary ingredients. Ingeneral, the compositions are prepared by uniformly and intimatelyadmixing the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product intothe desired presentation. For example, a tablet can be prepared bycompression or molding, optionally with one or more accessoryingredients. Compressed tablets can be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such aspowder or granules, optionally mixed with an excipient such as, but notlimited to, a binder, a lubricant, an inert diluent, and/or a surfaceactive or dispersing agent. Molded tablets can be made by molding in asuitable machine a mixture of the powdered compound moistened with aninert liquid diluent.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising an active ingredient, since water canfacilitate the degradation of some compounds. For example, water may beadded (e.g., 5%) in the pharmaceutical arts as a means of simulatinglong-term storage in order to determine characteristics such asshelf-life or the stability of formulations over time. Anhydrouspharmaceutical compositions and dosage forms of the invention can beprepared using anhydrous or low moisture containing ingredients and lowmoisture or low humidity conditions. Pharmaceutical compositions anddosage forms of the invention which contain lactose can be madeanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected. An anhydrouspharmaceutical composition may be prepared and stored such that itsanhydrous nature is maintained. Accordingly, anhydrous compositions maybe packaged using materials known to prevent exposure to water such thatthey can be included in suitable formulary kits. Examples of suitablepackaging include, but are not limited to, hermetically sealed foils,plastic or the like, unit dose containers, blister packs, and strippacks.

An active ingredient can be combined in an intimate admixture with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier can take a wide variety of formsdepending on the form of preparation desired for administration. Inpreparing the compositions for an oral dosage form, any of the usualpharmaceutical media can be employed as carriers, such as, for example,water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents, and the like in the case of oral liquid preparations(such as suspensions, solutions, and elixirs) or aerosols; or carrierssuch as starches, sugars, micro-crystalline cellulose, diluents,granulating agents, lubricants, binders, and disintegrating agents canbe used in the case of oral solid preparations, in some embodimentswithout employing the use of lactose. For example, suitable carriersinclude powders, capsules, and tablets, with the solid oralpreparations. If desired, tablets can be coated by standard aqueous ornonaqueous techniques.

Binders suitable for use in pharmaceutical compositions and dosage formsinclude, but are not limited to, corn starch, potato starch, or otherstarches, gelatin, natural and synthetic gums such as acacia, sodiumalginate, alginic acid, other alginates, powdered tragacanth, guar gum,cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixturesthereof.

Examples of suitable fillers for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

Disintegrants may be used in the compositions of the invention toprovide tablets that disintegrate when exposed to an aqueousenvironment. Too much of a disintegrant may produce tablets which maydisintegrate in the bottle. Too little may be insufficient fordisintegration to occur and may thus alter the rate and extent ofrelease of the active ingredient(s) from the dosage form. Thus, asufficient amount of disintegrant that is neither too little nor toomuch to detrimentally alter the release of the active ingredient(s) maybe used to form the dosage forms of the compounds disclosed herein. Theamount of disintegrant used may vary based upon the type of formulationand mode of administration, and may be readily discernible to those ofordinary skill in the art. About 0.5 to about 15 weight percent ofdisintegrant, or about 1 to about 5 weight percent of disintegrant, maybe used in the pharmaceutical composition. Disintegrants that can beused to form pharmaceutical compositions and dosage forms of theinvention include, but are not limited to, agar-agar, alginic acid,calcium carbonate, microcrystalline cellulose, croscarmellose sodium,crospovidone, polacrilin potassium, sodium starch glycolate, potato ortapioca starch, other starches, pre-gelatinized starch, other starches,clays, other algins, other celluloses, gums or mixtures thereof.

Lubricants which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, ormixtures thereof. Additional lubricants include, for example, a syloidsilica gel, a coagulated aerosol of synthetic silica, or mixturesthereof. A lubricant can optionally be added, in an amount of less thanabout 1 weight percent of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oraladministration, the active ingredient therein may be combined withvarious sweetening or flavoring agents, coloring matter or dyes and, ifso desired, emulsifying and/or suspending agents, together with suchdiluents as water, ethanol, propylene glycol, glycerin and variouscombinations thereof.

The tablets can be uncoated or coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed. Formulations for oral use can also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example, peanut oil, liquidparaffin or olive oil.

Surfactant which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to,hydrophilic surfactants, lipophilic surfactants, and mixtures thereof.That is, a mixture of hydrophilic surfactants may be employed, a mixtureof lipophilic surfactants may be employed, or a mixture of at least onehydrophilic surfactant and at least one lipophilic surfactant may beemployed.

A suitable hydrophilic surfactant may generally have an HLB value of atleast 10, while suitable lipophilic surfactants may generally have anHLB value of or less than about 10. An empirical parameter used tocharacterize the relative hydrophilicity and hydrophobicity of non-ionicamphiphilic compounds is the hydrophilic-lipophilic balance (“HLB”value). Surfactants with lower HLB values are more lipophilic orhydrophobic, and have greater solubility in oils, while surfactants withhigher HLB values are more hydrophilic, and have greater solubility inaqueous solutions. Hydrophilic surfactants are generally considered tobe those compounds having an HLB value greater than about 10, as well asanionic, cationic, or zwitterionic compounds for which the HLB scale isnot generally applicable. Similarly, lipophilic (i.e., hydrophobic)surfactants are compounds having an HLB value equal to or less thanabout 10. However, HLB value of a surfactant is merely a rough guidegenerally used to enable formulation of industrial, pharmaceutical andcosmetic emulsions.

Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionicsurfactants include, but are not limited to, alkylammonium salts;fusidic acid salts; fatty acid derivatives of amino acids,oligopeptides, and polypeptides; glyceride derivatives of amino acids,oligopeptides, and polypeptides; lecithins and hydrogenated lecithins;lysolecithins and hydrogenated lysolecithins; phospholipids andderivatives thereof; lysophospholipids and derivatives thereof;carnitine fatty acid ester salts; salts of alkylsulfates; fatty acidsalts; sodium docusate; acyl lactylates; mono- and di-acetylatedtartaric acid esters of mono- and di-glycerides; succinylated mono- anddi-glycerides; citric acid esters of mono- and di-glycerides; andmixtures thereof.

Within the aforementioned group, ionic surfactants include, by way ofexample: lecithins, lysolecithin, phospholipids, lysophospholipids andderivatives thereof; carnitine fatty acid ester salts; salts ofalkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono-and di-acetylated tartaric acid esters of mono- and di-glycerides;succinylated mono- and di-glycerides; citric acid esters of mono- anddi-glycerides; and mixtures thereof.

Ionic surfactants may be the ionized forms of lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholylsarcosine, caproate, caprylate,caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate,linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate,lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, andsalts and mixtures thereof.

Hydrophilic non-ionic surfactants may include, but are not limited to,alkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; polyoxyalkylene alkyl ethers such as polyethyleneglycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethyleneglycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esterssuch as polyethylene glycol fatty acids monoesters and polyethyleneglycol fatty acids diesters; polyethylene glycol glycerol fatty acidesters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fattyacid esters such as polyethylene glycol sorbitan fatty acid esters;hydrophilic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylenesterols, derivatives, and analogues thereof; polyoxyethylated vitaminsand derivatives thereof; polyoxyethylene-polyoxypropylene blockcopolymers; and mixtures thereof; polyethylene glycol sorbitan fattyacid esters and hydrophilic transesterification products of a polyolwith at least one member of the group consisting of triglycerides,vegetable oils, and hydrogenated vegetable oils. The polyol may beglycerol, ethylene glycol, polyethylene glycol, sorbitol, propyleneglycol, pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation,PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate,PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryllaurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenatedcastor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitanlaurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearylether, tocopheryl PEG-100 succinate, PEG-24 cholesterol,polyglyceryl-10oleate, Tween 40, Tween 60, sucrose monostearate, sucrosemonolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG15-100 octyl phenol series, and poloxamers.

Suitable lipophilic surfactants include, by way of example only: fattyalcohols; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lower alcohol fatty acids esters; propylene glycol fatty acidesters; sorbitan fatty acid esters; polyethylene glycol sorbitan fattyacid esters; sterols and sterol derivatives; polyoxyethylated sterolsand sterol derivatives; polyethylene glycol alkyl ethers; sugar esters;sugar ethers; lactic acid derivatives of mono- and di-glycerides;hydrophobic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids and sterols; oil-solublevitamins/vitamin derivatives; and mixtures thereof. Within this group,preferred lipophilic surfactants include glycerol fatty acid esters,propylene glycol fatty acid esters, and mixtures thereof, or arehydrophobic transesterification products of a polyol with at least onemember of the group consisting of vegetable oils, hydrogenated vegetableoils, and triglycerides.

In one embodiment, the composition may include a solubilizer to ensuregood solubilization and/or dissolution of the compound of the presentinvention and to minimize precipitation of the compound of the presentinvention. This can be especially important for compositions fornon-oral use, e.g., compositions for injection. A solubilizer may alsobe added to increase the solubility of the hydrophilic drug and/or othercomponents, such as surfactants, or to maintain the composition as astable or homogeneous solution or dispersion.

Examples of suitable solubilizers include, but are not limited to, thefollowing: alcohols and polyols, such as ethanol, isopropanol, butanol,benzyl alcohol, ethylene glycol, propylene glycol, butanediols andisomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropyleneglycol, polyvinylalcohol, hydroxypropyl methylcellulose and othercellulose derivatives, cyclodextrins and cyclodextrin derivatives;ethers of polyethylene glycols having an average molecular weight ofabout 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether(glycofurol) or methoxy PEG ; amides and other nitrogen-containingcompounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam,N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esterssuch as ethyl propionate, tributylcitrate, acetyl triethylcitrate,acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate,ethyl butyrate, triacetin, propylene glycol monoacetate, propyleneglycol diacetate, ε-caprolactone and isomers thereof, 6-valerolactoneand isomers thereof, 3-butyrolactone and isomers thereof; and othersolubilizers known in the art, such as dimethyl acetamide, dimethylisosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycolmonoethyl ether, and water.

Mixtures of solubilizers may also be used. Examples include, but notlimited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol,transcutol, propylene glycol, and dimethyl isosorbide. Particularlypreferred solubilizers include sorbitol, glycerol, triacetin, ethylalcohol, PEG-400, glycofurol and propylene glycol.

The amount of solubilizer that can be included is not particularlylimited. The amount of a given solubilizer may be limited to abioacceptable amount, which may be readily determined by one of skill inthe art. In some circumstances, it may be advantageous to includeamounts of solubilizers far in excess of bioacceptable amounts, forexample to maximize the concentration of the drug, with excesssolubilizer removed prior to providing the composition to a subjectusing conventional techniques, such as distillation or evaporation.Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%,50%, 100%, or up to about 200% by weight, based on the combined weightof the drug, and other excipients. If desired, very small amounts ofsolubilizer may also be used, such as 5%, 2%, 1% or even less.Typically, the solubilizer may be present in an amount of about 1% toabout 100%, more typically about 5% to about 25% by weight.

The composition can further include one or more pharmaceuticallyacceptable additives and excipients. Such additives and excipientsinclude, without limitation, detackifiers, anti-foaming agents,buffering agents, polymers, antioxidants, preservatives, chelatingagents, viscomodulators, tonicifiers, flavorants, colorants, odorants,opacifiers, suspending agents, binders, fillers, plasticizers,lubricants, and mixtures thereof.

In addition, an acid or a base may be incorporated into the compositionto facilitate processing, to enhance stability, or for other reasons.Examples of pharmaceutically acceptable bases include amino acids, aminoacid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide,sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate,magnesium hydroxide, magnesium aluminum silicate, synthetic aluminumsilicate, synthetic hydrocalcite, magnesium aluminum hydroxide,diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine,triethylamine, triisopropanolamine, trimethylamine,tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable arebases that are salts of a pharmaceutically acceptable acid, such asacetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonicacid, amino acids, ascorbic acid, benzoic acid, boric acid, butyricacid, carbonic acid, citric acid, fatty acids, formic acid, fumaricacid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lacticacid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionicacid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinicacid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonicacid, uric acid, and the like. Salts of polyprotic acids, such as sodiumphosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphatecan also be used. When the base is a salt, the cation can be anyconvenient and pharmaceutically acceptable cation, such as ammonium,alkali metals, alkaline earth metals, and the like. Example may include,but not limited to, sodium, potassium, lithium, magnesium, calcium andammonium.

Suitable acids are pharmaceutically acceptable organic or inorganicacids. Examples of suitable inorganic acids include hydrochloric acid,hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boricacid, phosphoric acid, and the like. Examples of suitable organic acidsinclude acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid, uric acid and the like.

Pharmaceutical Compositions for Injection.

In some embodiments, the invention provides a pharmaceutical compositionfor injection containing a compound of the present invention and apharmaceutical excipient suitable for injection. Components and amountsof agents in the compositions are as described herein.

The forms in which the novel compositions of the present invention maybe incorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and thelike (and suitable mixtures thereof), cyclodextrin derivatives, andvegetable oils may also be employed. The proper fluidity can bemaintained, for example, by the use of a coating, such as lecithin, forthe maintenance of the required particle size in the case of dispersionand by the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating the compoundof the present invention in the required amount in the appropriatesolvent with various other ingredients as enumerated above, as required,followed by filtered sterilization. Generally, dispersions are preparedby incorporating the various sterilized active ingredients into asterile vehicle which contains the basic dispersion medium and therequired other ingredients from those enumerated above. In the case ofsterile powders for the preparation of sterile injectable solutions,certain desirable methods of preparation are vacuum-drying andfreeze-drying techniques which yield a powder of the active ingredientplus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Pharmaceutical Compositions for Topical (e.g., Transdermal) Delivery.

In some embodiments, the invention provides a pharmaceutical compositionfor transdermal delivery containing a compound of the present inventionand a pharmaceutical excipient suitable for transdermal delivery.

Compositions of the present invention can be formulated intopreparations in solid, semi-solid, or liquid forms suitable for local ortopical administration, such as gels, water soluble jellies, creams,lotions, suspensions, foams, powders, slurries, ointments, solutions,oils, pastes, suppositories, sprays, emulsions, saline solutions,dimethylsulfoxide (DMSO)-based solutions. In general, carriers withhigher densities are capable of providing an area with a prolongedexposure to the active ingredients. In contrast, a solution formulationmay provide more immediate exposure of the active ingredient to thechosen area.

The pharmaceutical compositions also may comprise suitable solid or gelphase carriers or excipients, which are compounds that allow increasedpenetration of, or assist in the delivery of, therapeutic moleculesacross the stratum corneum permeability barrier of the skin. There aremany of these penetration-enhancing molecules known to those trained inthe art of topical formulation. Examples of such carriers and excipientsinclude, but are not limited to, humectants (e.g., urea), glycols (e.g.,propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleicacid), surfactants (e.g., isopropyl myristate and sodium laurylsulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes(e.g., menthol), amines, amides, alkanes, alkanols, water, calciumcarbonate, calcium phosphate, various sugars, starches, cellulosederivatives, gelatin, and polymers such as polyethylene glycols.

Another exemplary formulation for use in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of a compound of the present invention in controlled amounts,either with or without another agent.

The construction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art. See, e.g., U.S. Pat.Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructedfor continuous, pulsatile, or on demand delivery of pharmaceuticalagents.

Pharmaceutical Compositions for Inhalation.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices that deliver the formulationin an appropriate manner.

Other Pharmaceutical Compositions.

Pharmaceutical compositions may also be prepared from compositionsdescribed herein and one or more pharmaceutically acceptable excipientssuitable for sublingual, buccal, rectal, intraosseous, intraocular,intranasal, epidural, or intraspinal administration. Preparations forsuch pharmaceutical compositions are well-known in the art. See, e.g.,See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G,eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002;Pratt and Taylor, eds., Principles of Drug Action, Third Edition,Churchill Livingston, New York, 1990; Katzung, ed., Basic and ClinicalPharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman,eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGrawHill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., LippincottWilliams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia,Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all ofwhich are incorporated by reference herein in their entirety.

Administration of the compounds or pharmaceutical composition of thepresent invention can be effected by any method that enables delivery ofthe compounds to the site of action. These methods include oral routes,intraduodenal routes, parenteral injection (including intravenous,intraarterial, subcutaneous, intramuscular, intravascular,intraperitoneal or infusion), topical (e.g. transdermal application),rectal administration, via local delivery by catheter or stent orthrough inhalation. Compounds can also be administered intraadiposallyor intrathecally.

The amount of the compound administered will be dependent on the subjectbeing treated, the severity of the disorder or condition, the rate ofadministration, the disposition of the compound and the discretion ofthe prescribing physician. However, an effective dosage is in the rangeof about 0.001 to about 100 mg per kg body weight per day, preferablyabout 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kghuman, this would amount to about 0.05 to 7 g/day, preferably about 0.05to about 2.5 g/day. In some instances, dosage levels below the lowerlimit of the aforesaid range may be more than adequate, while in othercases still larger doses may be employed without causing any harmfulside effect, e.g. by dividing such larger doses into several small dosesfor administration throughout the day.

In some embodiments, a compound of the invention is administered in asingle dose. Typically, such administration will be by injection, e.g.,intravenous injection, in order to introduce the agent quickly. However,other routes may be used as appropriate. A single dose of a compound ofthe invention may also be used for treatment of an acute condition.

In some embodiments, a compound of the invention is administered inmultiple doses. Dosing may be about once, twice, three times, fourtimes, five times, six times, or more than six times per day. Dosing maybe about once a month, once every two weeks, once a week, or once everyother day. In another embodiment a compound of the invention and anotheragent are administered together about once per day to about 6 times perday. In another embodiment the administration of a compound of theinvention and an agent continues for less than about 7 days. In yetanother embodiment the administration continues for more than about 6,10, 14, 28 days, two months, six months, or one year. In some cases,continuous dosing is achieved and maintained as long as necessary.

Administration of the compounds of the invention may continue as long asnecessary. In some embodiments, a compound of the invention isadministered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In someembodiments, a compound of the invention is administered for less than28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound ofthe invention is administered chronically on an ongoing basis, e.g., forthe treatment of chronic effects.

An effective amount of a compound of the invention may be administeredin either single or multiple doses by any of the accepted modes ofadministration of agents having similar utilities, including rectal,buccal, intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, or as an inhalant.

The compositions of the invention may also be delivered via animpregnated or coated device such as a stent, for example, or anartery-inserted cylindrical polymer. Such a method of administrationmay, for example, aid in the prevention or amelioration of restenosisfollowing procedures such as balloon angioplasty. Without being bound bytheory, compounds of the invention may slow or inhibit the migration andproliferation of smooth muscle cells in the arterial wall whichcontribute to restenosis. A compound of the invention may beadministered, for example, by local delivery from the struts of a stent,from a stent graft, from grafts, or from the cover or sheath of a stent.In some embodiments, a compound of the invention is admixed with amatrix. Such a matrix may be a polymeric matrix, and may serve to bondthe compound to the stent. Polymeric matrices suitable for such use,include, for example, lactone-based polyesters or copolyesters such aspolylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides,polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester)copolymers (e.g. PEO-PLLA); polydimethylsiloxane,poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g.polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone),fluorinated polymers such as polytetrafluoroethylene and celluloseesters. Suitable matrices may be nondegrading or may degrade with time,releasing the compound or compounds. Compounds of the invention may beapplied to the surface of the stent by various methods such as dip/spincoating, spray coating, dip-coating, and/or brush-coating. The compoundsmay be applied in a solvent and the solvent may be allowed to evaporate,thus forming a layer of compound onto the stent. Alternatively, thecompound may be located in the body of the stent or graft, for examplein microchannels or micropores. When implanted, the compound diffusesout of the body of the stent to contact the arterial wall. Such stentsmay be prepared by dipping a stent manufactured to contain suchmicropores or microchannels into a solution of the compound of theinvention in a suitable solvent, followed by evaporation of the solvent.Excess drug on the surface of the stent may be removed via an additionalbrief solvent wash. In yet other embodiments, compounds of the inventionmay be covalently linked to a stent or graft. A covalent linker may beused which degrades in vivo, leading to the release of the compound ofthe invention. Any bio-labile linkage may be used for such a purpose,such as ester, amide or anhydride linkages. Compounds of the inventionmay additionally be administered intravascularly from a balloon usedduring angioplasty. Extravascular administration of the compounds viathe pericard or via advential application of formulations of theinvention may also be performed to decrease restenosis.

A variety of stent devices which may be used as described are disclosed,for example, in the following references, all of which are herebyincorporated by reference: U.S. Pat. No. 5,451,233; U.S. Pat. No.5,040,548; U.S. Pat. No. 5,061,273; U.S. Pat. No. 5,496,346; U.S. Pat.No. 5,292,331; U.S. Pat. No. 5,674,278; U.S. Pat. No. 3,657,744; U.S.Pat. No. 4,739,762; U.S. Pat. No. 5,195,984; U.S. Pat. No. 5,292,331;U.S. Pat. No. 5,674,278; U.S. Pat. No. 5,879,382; U.S. Pat. No.6,344,053.

The compounds of the invention may be administered in dosages. It isknown in the art that due to intersubject variability in compoundpharmacokinetics, individualization of dosing regimen is necessary foroptimal therapy. Dosing for a compound of the invention may be found byroutine experimentation in light of the instant disclosure.

When a compound of the invention is administered in a composition thatcomprises one or more agents, and the agent has a shorter half-life thanthe compound of the invention unit dose forms of the agent and thecompound of the invention may be adjusted accordingly.

The subject pharmaceutical composition may, for example, be in a formsuitable for oral administration as a tablet, capsule, pill, powder,sustained release formulations, solution, suspension, for parenteralinjection as a sterile solution, suspension or emulsion, for topicaladministration as an ointment or cream or for rectal administration as asuppository. The pharmaceutical composition may be in unit dosage formssuitable for single administration of precise dosages. Thepharmaceutical composition will include a conventional pharmaceuticalcarrier or excipient and a compound according to the invention as anactive ingredient. In addition, it may include other medicinal orpharmaceutical agents, carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compound in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

The invention also provides kits. The kits include a compound orcompounds of the present invention as described herein, in suitablepackaging, and written material that can include instructions for use,discussion of clinical studies, listing of side effects, and the like.Such kits may also include information, such as scientific literaturereferences, package insert materials, clinical trial results, and/orsummaries of these and the like, which indicate or establish theactivities and/or advantages of the composition, and/or which describedosing, administration, side effects, drug interactions, or otherinformation useful to the health care provider. Such information may bebased on the results of various studies, for example, studies usingexperimental animals involving in vivo models and studies based on humanclinical trials. The kit may further contain another agent. In someembodiments, the compound of the present invention and the agent areprovided as separate compositions in separate containers within the kit.In some embodiments, the compound of the present invention and the agentare provided as a single composition within a container in the kit.Suitable packaging and additional articles for use (e.g., measuring cupfor liquid preparations, foil wrapping to minimize exposure to air, andthe like) are known in the art and may be included in the kit. Kitsdescribed herein can be provided, marketed and/or promoted to healthproviders, including physicians, nurses, pharmacists, formularyofficials, and the like. Kits may also, in some embodiments, be marketeddirectly to the consumer.

The invention also provides methods of using the compounds orpharmaceutical compositions of the present invention to treat diseaseconditions, including but not limited to conditions implicated bymTORC1, mTORC2 and/or PI3-kinases malfunction.

The invention also relates to a method of treating a hyperproliferativedisorder in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrateor derivative thereof. In some embodiments, said method relates to thetreatment of cancer such as acute myeloid leukemia, thymus, brain, lung,squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oralcavity and oropharyngeal, bladder, gastric, stomach, pancreatic,bladder, breast, cervical, head, neck, renal, kidney, liver, ovarian,prostate, colorectal, esophageal, testicular, gynecological, thyroid,CNS, PNS, AIDS related (e.g. Lymphoma and Kaposi's Sarcoma) orViral-Induced cancer. In some embodiments, said method relates to thetreatment of a non-cancerous hyperproliferative disorder such as benignhyperplasia of the skin (e.g., psoriasis), restenosis, or prostate(e.g., benign prostatic hypertrophy (BPH)).

The treatment methods provided herein comprise administering to thesubject a therapeutically effective amount of a compound of theinvention. In one embodiment, the present invention provides a method oftreating an inflammation disorder, including autoimmune diseases in amammal. The method comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrateor derivative thereof. diseases associated with malfunctioning of one ormore types of mTOR (including Examples of autoimmune diseases includesbut is are not limited to acute disseminated encephalomyelitis (ADEM),Addison's disease, antiphospholipid antibody syndrome (APS), aplasticanemia, autoimmune hepatitis, coeliac disease, Crohn's disease, Diabetesmellitus (type 1), Goodpasture's syndrome, Graves' disease,Guillain-Barré syndrome (GBS), Hashimoto's disease, lupus erythematosus,multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome(OMS), optic neuritis, Ord's thyroiditis, oemphigus, polyarthritis,primary biliary cirrhosis, psoriasis, rheumatoid arthritis, Reiter'ssyndrome, Takayasu's arteritis, temporal arteritis (also known as “giantcell arteritis”), warm autoimmune hemolytic anemia, Wegener'sgranulomatosis, alopecia universalis, Chagas' disease, chronic fatiguesyndrome, dysautonomia, endometriosis, hidradenitis suppurativa,interstitial cystitis, neuromyotonia, sarcoidosis, scleroderma,ulcerative colitis, vitiligo, and vulvodynia. Other disorders includebone-resorption disorders and thrombosis.

In some embodiments, the method of treating inflammatory or autoimmunediseases comprises administering to a subject (e.g. a mammal) atherapeutically effective amount of one or more compounds of the presentinvention that selectively inhibit PI3K-δ and/or PI3K-γ as compared toall other type I PI3 kinases. Such selective inhibition of PI3K-6 and/orPI3K-γ may be advantageous for treating any of the diseases orconditions described herein. For example, selective inhibition of PI3K-δmay inhibit inflammatory responses associated with inflammatorydiseases, autoimmune disease, or diseases related to an undesirableimmune response including but not limited to asthma, emphysema, allergy,dermatitis, rhuematoid arthritis, psoriasis, lupus erythematosus, orgraft versus host disease. Selective inhibition of PI3K-δ may furtherprovide for a reduction in the inflammatory or undesirable immuneresponse without a concomittant reduction in the ability to reduce abacterial, viral, and/or fungal infection. Selective inhibition of bothPI3K-δ and PI3K-γ may be advantageous for inhibiting the inflammatoryresponse in the subject to a greater degree than that would be providedfor by inhibitors that selectively inhibit PI3K-δ or PI3K-γ alone. Inone aspect, one or more of the subject methods are effective in reducingantigen specific antibody production in vivo by about 2-fold, 3-fold,4-fold, 5-fold, 7.5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 250-fold,500-fold, 750-fold, or about 1000-fold or more. In another aspect, oneor more of the subject methods are effective in reducing antigenspecific IgG3 and/or IgGM production in vivo by about 2-fold, 3-fold,4-fold, 5-fold, 7.5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 250-fold,500-fold, 750-fold, or about 1000-fold or more.

In one aspect, one of more of the subject methods are effective inameliorating symptoms associated with rhuematoid arthritis including butnot limited to a reduction in the swelling of joints, a reduction inserum anti-collagen levels, and/or a reduction in joint pathology suchas bone resorption, cartilage damage, pannus, and/or inflammation. Inanother aspect, the subject methods are effective in reducing ankleinflammation by at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 50%,60%, or about 75% to 90%. In another aspect, the subject methods areeffective in reducing knee inflammation by at least about 2%, 5%, 10%,15%, 20%, 25%, 30%, 50%, 60%, or about 75% to 90% or more. In stillanother aspect, the subject methods are effective in reducing serumanti-type II collagen levels by at least about 10%, 12%, 15%, 20%, 24%,25%, 30%, 35%, 50%, 60%, 75%, 80%, 86%, 87%, or about 90% or more. Inanother aspect, the subject methods are effective in reducing anklehistopathology scores by about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%,60%, 75%, 80%, 90% or more. In still another aspect, the subject methodsare effective in reducing knee histopathology scores by about 5%, 10%,15%, 20%, 25%, 30%, 40%, 50%, 60%, 75%, 80%, 90% or more.

In other embodiments, the present invention provides methods of usingthe compounds or pharmaceutical compositions to treat respiratorydiseases including but not limited to diseases affecting the lobes oflung, pleural cavity, bronchial tubes, trachea, upper respiratory tract,or the nerves and muscle for breathing. For example, methods areprovided to treat obstructive pulmonary disease. Chronic obstructivepulmonary disease (COPD) is an umbrella term for a group of respiratorytract diseases that are characterized by airflow obstruction orlimitation. Conditions included in this umbrella term are: chronicbronchitis, emphysema, and bronchiectasis.

In another embodiment, the compounds described herein are used for thetreatment of asthma. Also, the compounds or pharmaceutical compositionsdescribed herein may be used for the treatment of endotoxemia andsepsis. In one embodiment, the compounds or pharmaceutical compositionsdescribed herein are used to for the treatment of rheumatoid arthritis(RA). In yet another embodiment, the compounds or pharmaceuticalcompositions described herein is used for the treatment of contact oratopic dermatitis. Contact dermatitis includes irritant dermatitis,phototoxic dermatitis, allergic dermatitis, photoallergic dermatitis,contact urticaria, systemic contact-type dermatitis and the like.Irritant dermatitis can occur when too much of a substance is used onthe skin of when the skin is sensitive to certain substance. Atopicdermatitis, sometimes called eczema, is a kind of dermatitis, an atopicskin disease.

The invention also relates to a method of treating diseases related tovasculogenesis or angiogenesis in a mammal that comprises administeringto said mammal a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt, ester, prodrug,solvate, hydrate or derivative thereof. In some embodiments, said methodis for treating a disease selected from the group consisting of tumorangiogenesis, chronic inflammatory disease such as rheumatoid arthritis,atherosclerosis, inflammatory bowel disease, skin diseases such aspsoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy,retinopathy of prematurity, age-related macular degeneration,hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast,lung, pancreatic, prostate, colon and epidermoid cancer.

Subjects that can be treated with compounds of the invention, orpharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative of said compounds, according to the methods of this inventioninclude, for example, subjects that have been diagnosed as havingpsoriasis; restenosis; atherosclerosis; BPH; breast cancer such as aductal carcinoma in duct tissue in a mammary gland, medullarycarcinomas, colloid carcinomas, tubular carcinomas, and inflammatorybreast cancer; ovarian cancer, including epithelial ovarian tumors suchas adenocarcinoma in the ovary and an adenocarcinoma that has migratedfrom the ovary into the abdominal cavity; uterine cancer; cervicalcancer such as adenocarcinoma in the cervix epithelial includingsquamous cell carcinoma and adenocarcinomas; prostate cancer, such as aprostate cancer selected from the following: an adenocarcinoma or anadenocarcinoma that has migrated to the bone; pancreatic cancer such asepitheloid carcinoma in the pancreatic duct tissue and an adenocarcinomain a pancreatic duct; bladder cancer such as a transitional cellcarcinoma in urinary bladder, urothelial carcinomas (transitional cellcarcinomas), tumors in the urothelial cells that line the bladder,squamous cell carcinomas, adenocarcinomas, and small cell cancers;leukemia such as acute myeloid leukemia (AML), acute lymphocyticleukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairycell leukemia, myelodysplasia, myeloproliferative disorders, acutemyelogenous leukemia (AML), chronic myelogenous leukemia (CML),mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM),and myelodysplastic syndrome (MDS); bone cancer; lung cancer such asnon-small cell lung cancer (NSCLC), which is divided into squamous cellcarcinomas, adenocarcinomas, and large cell undifferentiated carcinomas,and small cell lung cancer; skin cancer such as basal cell carcinoma,melanoma, squamous cell carcinoma and actinic keratosis, which is a skincondition that sometimes develops into squamous cell carcinoma; eyeretinoblastoma; cutaneous or intraocular (eye) melanoma; primary livercancer (cancer that begins in the liver); kidney cancer; thyroid cancersuch as papillary, follicular, medullary and anaplastic; AIDS-relatedlymphoma such as diffuse large B-cell lymphoma, B-cell immunoblasticlymphoma and small non-cleaved cell lymphoma; Kaposi's Sarcoma;viral-induced cancers including hepatitis B virus (HBV), hepatitis Cvirus (HCV), and hepatocellular carcinoma; human lymphotrophicvirus-type 1 (HTLV-1) and adult T-cell leukemia/lymphoma; and humanpapilloma virus (HPV) and cervical cancer; central nervous systemcancers (CNS) such as primary brain tumor, which includes gliomas(astrocytoma, anaplastic astrocytoma, or glioblastoma multiforme),Oligodendroglioma, Ependymoma, Meningioma, Lymphoma, Schwannoma, andMedulloblastoma; peripheral nervous system (PNS) cancers such asacoustic neuromas and malignant peripheral nerve sheath tumor (MPNST)including neurofibromas and schwannomas, malignant fibrous cytoma,malignant fibrous histiocytoma, malignant meningioma, malignantmesothelioma, and malignant mixed Müllerian tumor; oral cavity andoropharyngeal cancer such as, hypopharyngeal cancer, laryngeal cancer,nasopharyngeal cancer, and oropharyngeal cancer; stomach cancer such aslymphomas, gastric stromal tumors, and carcinoid tumors; testicularcancer such as germ cell tumors (GCTs), which include seminomas andnonseminomas, and gonadal stromal tumors, which include Leydig celltumors and Sertoli cell tumors; thymus cancer such as to thymomas,thymic carcinomas, Hodgkin disease, non-Hodgkin lymphomas carcinoids orcarcinoid tumors; rectal cancer; and colon cancer

The invention also relates to a method of treating diabetes in a mammalthat comprises administering to said mammal a therapeutically effectiveamount of a compound of the invention, or a pharmaceutically acceptablesalt, ester, prodrug, solvate, hydrate or derivative thereof.

In addition, the compounds described herein may be used to treat acne.

In addition, the compounds described herein may be used for thetreatment of arteriosclerosis, including atherosclerosis.Arteriosclerosis is a general term describing any hardening of medium orlarge arteries. Atherosclerosis is a hardening of an artery specificallydue to an atheromatous plaque.

Further the compounds described herein may be used for the treatment ofglomerulonephritis. Glomerulonephritis is a primary or secondaryautoimmune renal disease characterized by inflammation of the glomeruli.It may be asymptomatic, or present with hematuria and/or proteinuria.There are many recognized types, divided in acute, subacute or chronicglomerulonephritis. Causes are infectious (bacterial, viral or parasiticpathogens), autoimmune or paraneoplastic.

Additionally, the compounds described herein may be used for thetreatment of bursitis, lupus, acute disseminated encephalomyelitis(ADEM), addison's disease, antiphospholipid antibody syndrome (APS),aplastic anemia, autoimmune hepatitis, coeliac disease, crohn's disease, diabetes mellitus (type 1), goodpasture's syndrome, graves' disease,guillain-barré syndrome (GBS), hashimoto's disease, inflammatory boweldisease, lupus erythematosus, myasthenia gravis, opsoclonus myoclonussyndrome (OMS), optic neuritis, ord's thyroiditis, ostheoarthritis,uveoretinitis, pemphigus, polyarthritis, primary biliary cirrhosis,reiter's syndrome, takayasu's arteritis, temporal arteritis, warmautoimmune hemolytic anemia, wegener's granulomatosis, alopeciauniversalis, chagas' disease, chronic fatigue syndrome, dysautonomia,endometriosis, hidradenitis suppurativa, interstitial cystitis,neuromyotonia, sarcoidosis, scleroderma, ulcerative colitis, vitiligo,vulvodynia, appendicitis, arteritis, arthritis, blepharitis,bronchiolitis, bronchitis, cervicitis, cholangitis, cholecystitis,chorioamnionitis, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,gastroenteritis, gingivitis, hepatitis, hidradenitis, ileitis , iritis,laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis,nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

The invention also relates to a method of treating a cardiovasculardisease in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the invention, or apharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative thereof. Examples of cardiovascular conditions include, butare not limited to, atherosclerosis, restenosis, vascular occlusion andcarotid obstructive disease.

In another aspect, the invention provides methods of disrupting thefunction of a leukocyte or disrupting a function of an osteoclast. Themethod includes contacting the leukocyte or the osteoclast with afunction disrupting amount of a compound of the invention.

In another aspect of the present invention, methods are provided fortreating ophthalmic disease by administering one or more compounds ofthe invention or pharmaceutical compositions to the eye of a subject.

Methods are further provided for administering the compounds of thepresent invention via eye drop, intraocular injection, intravitrealinjection, topically, or through the use of a drug eluting device,microcapsule, implant, or microfluidic device. In some cases, thecompounds of the present invention are administered with a carrier orexcipient that increases the intraocular penetrance of the compound suchas an oil and water emulsion with colloid particles having an oily coresurrounded by an interfacial film. It is contemplated that all localroutes to the eye may be used including topical, subconjunctival,periocular, retrobulbar, subtenon, intracameral, intravitreal,intraocular, subretinal, juxtascleral and suprachoroidal administration.Systemic or parenteral administration may be feasible including but notlimited to intravenous, subcutaneous, and oral delivery. An exemplarymethod of administration will be intravitreal or subtenon injection ofsolutions or suspensions, or intravitreal or subtenon placement ofbioerodible or non-bioerodible devices, or by topical ocularadministration of solutions or suspensions, or posterior juxtascleraladministration of a gel or cream formulation.

In some cases, the colloid particles include at least one cationic agentand at least one non-ionic surfactant such as a poloxamer, tyloxapol, apolysorbate, a polyoxyethylene castor oil derivative, a sorbitan ester,or a polyoxyl stearate. In some cases, the cationic agent is analkylamine, a tertiary alkyl amine, a quaternary ammonium compound, acationic lipid, an amino alcohol, a biguanidine salt, a cationiccompound or a mixture thereof. In some cases the cationic agent is abiguanidine salt such as chlorhexidine, polyaminopropyl biguanidine,phenformin, alkylbiguanidine, or a mixture thereof. In some cases, thequaternary ammonium compound is a benzalkonium halide, lauralkoniumhalide, cetrimide, hexadecyltrimethylammonium halide,tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide,cetrimonium halide, benzethonium halide, behenalkonium halide,cetalkonium halide, cetethyldimonium halide, cetylpyridinium halide,benzododecinium halide, chlorallyl methenamine halide, rnyristylalkoniumhalide, stearalkonium halide or a mixture of two or more thereof. Insome cases, cationic agent is a benzalkonium chloride, lauralkoniumchloride, benzododecinium bromide, benzethenium chloride,hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide,dodecyltrimethylammonium bromide or a mixture of two or more thereof. Insome cases, the oil phase is mineral oil and light mineral oil, mediumchain triglycerides (MCT), coconut oil; hydrogenated oils comprisinghydrogenated cottonseed oil, hydrogenated palm oil, hydrogenate castoroil or hydrogenated soybean oil; polyoxyethylene hydrogenated castor oilderivatives comprising poluoxyl-40 hydrogenated castor oil, polyoxyl-60hydrogenated castor oil or polyoxyl-100 hydrogenated castor oil.

The invention further provides methods of modulating a PI3K and/or mTorkinase activity by contacting the kinase with an effective amount of acompound of the invention. Modulation can be inhibiting or activatingkinase activity. In some embodiments, the invention provides methods ofinhibiting kinase activity by contacting the kinase with an effectiveamount of a compound of the invention in solution. In some embodiments,the invention provides methods of inhibiting the kinase activity bycontacting a cell, tissue, organ that express the kinase of interest. Insome embodiments, the invention provides methods of inhibiting kinaseactivity in subject including but not limited to rodents and mammal(e.g., human) by administering into the subject an effective amount of acompound of the invention. In some embodiments, the percentage ofinhibiting exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

In some embodiments, the kinase is selected from the group consisting ofmTor, including different isoforms such as mTORC1 and mTORC2; PI3 kinaseincluding different isorforms such as PI3 kinase α, PI3 kinase β, PI3kinase γ, PI3 kinase 6; DNA-PK; Abl, VEGFR, Ephrin receptor B4 (EphB4);TEK receptor tyrosine kinase (TIE2); FMS-related tyrosine kinase 3(FLT-3); Platelet derived growth factor receptor (PDGFR); RET; ATM; ATR;hSmg-1; Hck; Src; Epidermal growth factor receptor (EGFR); KIT; InsulinReceptor (1R) and IGFR.

The invention further provides methods of modulating mTOR activity bycontacting mTOR with an amount of a compound of the invention sufficientto modulate the activity of mTOR. Modulate can be inhibiting oractivating mTOR activity. In some embodiments, the invention providesmethods of inhibiting mTOR by contacting mTOR with an amount of acompound of the invention sufficient to inhibit the activity of mTOR. Insome embodiments, the invention provides methods of inhibiting mTORactivity in a solution by contacting said solution with an amount of acompound of the invention sufficient to inhibit the activity of mTOR insaid solution. In some embodiments, the invention provides methods ofinhibiting mTOR activity in a cell by contacting said cell with anamount of a compound of the invention sufficient to inhibit the activityof mTOR in said cell. In some embodiments, the invention providesmethods of inhibiting mTOR activity in a tissue by contacting saidtissue with an amount of a compound of the invention sufficient toinhibit the activity of mTOR in said tissue. In some embodiments, theinvention provides methods of inhibiting mTOR activity in an organism bycontacting said organism with an amount of a compound of the inventionsufficient to inhibit the activity of mTOR in said organism. In someembodiments, the invention provides methods of inhibiting mTOR activityin an animal by contacting said animal with an amount of a compound ofthe invention sufficient to inhibit the activity of mTOR in said animal.In some embodiments, the invention provides methods of inhibiting mTORactivity in a mammal by contacting said mammal with an amount of acompound of the invention sufficient to inhibit the activity of mTOR insaid mammal. In some embodiments, the invention provides methods ofinhibiting mTOR activity in a human by contacting said human with anamount of a compound of the invention sufficient to inhibit the activityof mTOR in said human. The present invention provides methods oftreating a disease mediated by mTOR activity in a subject in need ofsuch treatment.

The present invention also provides methods for combination therapies inwhich an agent known to modulate other pathways, or other components ofthe same pathway, or even overlapping sets of target enzymes are used incombination with a compound of the present invention, or apharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative thereof. In one aspect, such therapy includes but is notlimited to the combination of one or more compounds of the inventionwith chemotherapeutic agents, therapeutic antibodies, and radiationtreatment, to provide a synergistic or additive therapeutic effect.

In one aspect, the compounds or pharmaceutical compositions of theinvention may present synergistic or additive efficacy when administeredin combination with agents that inhibit IgE production or activity. Suchcombination can reduce the undesired effect of high level of IgEassociated with the use of one or more PI3Kδ inhibitors, if such effectoccurs. This may be particularly useful in treatment of autoimmune andinflammatory disorders (AIID) such as rheumatoid arthritis.Additionally, the administration of PI3Kδ or PI3Kδ/γ inhibitors of theinvention in combination with inhibitors of mTOR may also exhibitsynergy through enhanced inhibition of the PI3K pathway.

In a separate but related aspect, the invention provides a combinationtreatment of a disease associated with PI3Kδ comprising administering toa PI3Kδ□ inhibitor and an agent that inhibits IgE production oractivity. Other exemplary PI3Kδ□ inhibitors are applicable and they aredescribed, e.g., U.S. Pat. No. 6,800,620. Such combination treatment isparticularly useful for treating autoimmune and inflammatory diseases(AIID) including but not limited to rheumatoid arthritis.

Agents that inhibit IgE production are known in the art and they includebut are not limited to one or more of TEI-9874,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid,rapamycin, rapamycin analogs (i.e. rapalogs), TORC1 inhibitors, TORC2inhibitors, and any other compounds that inhibit mTORC1 and mTORC2.Agents that inhibit IgE activity include, for example, anti-IgEantibodies such as for example Omalizumab and TNX-901.

For treatment of autoimmune diseases, the compounds of the invention orpharmaceutical compositions can be used in combination with commonlyprescribed drugs including but not limited to Enbrel®, Remicade®,Humira®, Avonex®, and Rebif®. For treatment of respiratory diseases, thecompounds of the invention or pharmaceutical compositions can beadministered in combination with commonly prescribed drugs including butnot limited to Xolair®, Advair®, Singulair®, and Spiriva®.

The compounds of the invention may be formulated or administered inconjunction with other agents that act to relieve the symptoms ofinflammatory conditions such as encephalomyelitis, asthma, and the otherdiseases described herein. These agents include non-steroidalanti-inflammatory drugs (NSAIDs), e.g. acetylsalicylic acid; ibuprofen;naproxen; indomethacin; nabumetone; tolmetin; etc. Corticosteroids areused to reduce inflammation and suppress activity of the immune system.The most commonly prescribed drug of this type is Prednisone.Chloroquine (Aralen) or hydroxychloroquine (Plaquenil) may also be veryuseful in some individuals with lupus. They are most often prescribedfor skin and joint symptoms of lupus. Azathioprine (Imuran) andcyclophosphamide (Cytoxan) suppress inflammation and tend to suppressthe immune system. Other agents, e.g. methotrexate and cyclosporin areused to control the symptoms of lupus. Anticoagulants are employed toprevent blood from clotting rapidly. They range from aspirin at very lowdose which prevents platelets from sticking, to heparin/coumadin.

In another aspect, this invention also relates to methods andpharmaceutical compositions for inhibiting abnormal cell growth in amammal which comprises an amount of a compound of the invention, or apharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative thereof, in combination with an amount of an anti-canceragent (e.g. a chemotherapeutic agent). Many chemotherapeutics arepresently known in the art and can be used in combination with thecompounds of the invention.

In some embodiments, the chemotherapeutic is selected from the groupconsisting of mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.

Non-limiting examples are chemotherapeutic agents, cytotoxic agents, andnon-peptide small molecules such as Gleevec® (Imatinib Mesylate),Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), andAdriamycin as well as a host of chemotherapeutic agents. Non-limitingexamples of chemotherapeutic agents include alkylating agents such asthiotepa and cyclosphosphamide (CYTOXAN™); alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide and trimethylolomelamine; nitrogenmustards such as chlorambucil, chlornaphazine, cholophosphamide,estramustine, ifosfamide, mechlorethamine, mechlorethamine oxidehydrochloride, melphalan, novembichin, phenesterine, prednimustine,trofosfamide, uracil mustard; nitrosureas such as carmustine,chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine,bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin,carzinophilin, Casodex™, chromomycins, dactinomycin, daunorubicin,detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin,esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid,nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine,androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine;bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; etoglucid; galliumnitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone;mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinicacid; 2-ethylhydrazide; procarbazine; PSK.R™; razoxane; sizofuran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, e.g.paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, N.J.) anddocetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France); retinoicacid; esperamicins; capecitabine; and pharmaceutically acceptable salts,acids or derivatives of any of the above. Also included as suitablechemotherapeutic cell conditioners are anti-hormonal agents that act toregulate or inhibit hormone action on tumors such as anti-estrogensincluding for example tamoxifen, (Nolvadex™), raloxifene, aromataseinhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene,LY 117018, onapristone, and toremifene (Fareston); and anti-androgenssuch as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin;chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate;platinum analogs such as cisplatin and carboplatin; vinblastine;platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone;vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin;aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11);topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO). Wheredesired, the compounds or pharmaceutical composition of the presentinvention can be used in combination with commonly prescribedanti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®,Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab, Acridinecarboxamide, Adecatumumab, 17-N-Allylamino-17-demethoxygeldanamycin,Alpharadin, Alvocidib, 3-Aminopyridine-2-carboxaldehydethiosemicarbazone, Amonafide, Anthracenedione, Anti-CD22 immunotoxins,Antineoplastic, Antitumorigenic herbs, Apaziquone, Atiprimod,Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar,Brostallicin, Bryostatin, Buthionine sulfoximine, CBV (chemotherapy),Calyculin, cell-cycle nonspecific antineoplastic agents, Dichloroaceticacid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin,Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICEchemotherapy regimen, IT-101, Imexon, Imiquimod, Indolocarbazole,Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucanthone, Lurtotecan,Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, ortataxel,PAC-1, Pawpaw, Pixantrone, Proteasome inhibitor, Rebeccamycin,Resiquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, StanfordV, Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar,Tesetaxel, Triplatin tetranitrate, Tris(2-chloroethyl)amine,Troxacitabine, Uramustine, Vadimezan, Vinflunine, ZD6126, andZosuquidar.

This invention further relates to a method for using the compounds orpharmaceutical compositions provided herein, in combination withradiation therapy for inhibiting abnormal cell growth or treating thehyperproliferative disorder in the mammal. Techniques for administeringradiation therapy are known in the art, and these techniques can be usedin the combination therapy described herein. The administration of thecompound of the invention in this combination therapy can be determinedas described herein.

Radiation therapy can be administered through one of several methods, ora combination of methods, including without limitation external-beamtherapy, internal radiation therapy, implant radiation, stereotacticradiosurgery, systemic radiation therapy, radiotherapy and permanent ortemporary interstitial brachytherapy. The term “brachytherapy,” as usedherein, refers to radiation therapy delivered by a spatially confinedradioactive material inserted into the body at or near a tumor or otherproliferative tissue disease site. The term is intended withoutlimitation to include exposure to radioactive isotopes (e.g. At −211,I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, andradioactive isotopes of Lu). Suitable radiation sources for use as acell conditioner of the present invention include both solids andliquids. By way of non-limiting example, the radiation source can be aradionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source,I-125 as a solid source, or other radionuclides that emit photons, betaparticles, gamma radiation, or other therapeutic rays. The radioactivematerial can also be a fluid made from any solution of radionuclide(s),e.g., a solution of I-125 or I-131, or a radioactive fluid can beproduced using a slurry of a suitable fluid containing small particlesof solid radionuclides, such as Au-198, Y-90. Moreover, theradionuclide(s) can be embodied in a gel or radioactive micro spheres.

Without being limited by any theory, the compounds of the presentinvention can render abnormal cells more sensitive to treatment withradiation for purposes of killing and/or inhibiting the growth of suchcells. Accordingly, this invention further relates to a method forsensitizing abnormal cells in a mammal to treatment with radiation whichcomprises administering to the mammal an amount of a compound of thepresent invention or pharmaceutically acceptable salt, ester, prodrug,solvate, hydrate or derivative thereof, which amount is effective issensitizing abnormal cells to treatment with radiation. The amount ofthe compound, salt, or solvate in this method can be determinedaccording to the means for ascertaining effective amounts of suchcompounds described herein.

The compounds or pharmaceutical compositions of the invention can beused in combination with an amount of one or more substances selectedfrom anti-angiogenesis agents, signal transduction inhibitors,antiproliferative agents, glycolysis inhibitors, or autophagyinhibitors.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloproteinase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-11(cyclooxygenase 11) inhibitors, can be used in conjunction with acompound of the invention and pharmaceutical compositions describedherein. Anti-angiogenesis agents include, for example, rapamycin,temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, andbevacizumab. Examples of useful COX-II inhibitors include CELEBREX™(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrixmetalloproteinase inhibitors are described in WO 96/33172 (publishedOct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European PatentApplication No. 97304971.1 (filed Jul. 8, 1997), European PatentApplication No. 99308617.2 (filed Oct. 29, 1999), WO 98/07697 (publishedFeb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918(published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998), WO98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16,1998), European Patent Publication 606,046 (published Jul. 13, 1994),European Patent Publication 931, 788 (published Jul. 28, 1999), WO90/05719 (published May 31, 1990), WO 99/52910 (published Oct. 21,1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (publishedJun. 17, 1999), PCT International Application No. PCT/IB98/01113 (filedJul. 21, 1998), European Patent Application No. 99302232.1 (filed Mar.25, 1999), Great Britain Patent Application No. 9912961.1 (filed Jun. 3,1999), U.S. Provisional Application No. 60/148,464 (filed Aug. 12,1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No.5,861,510 (issued Jan. 19, 1999), and European Patent Publication780,386 (published Jun. 25, 1997), all of which are incorporated hereinin their entireties by reference. Preferred MMP-2 and MMP-9 inhibitorsare those that have little or no activity inhibiting MMP-1. Morepreferred, are those that selectively inhibit MMP-2 and/or AMP-9relative to the other matrix-metalloproteinases (i.e., MAP-1, MMP-3,MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).Some specific examples of MMP inhibitors useful in the invention areAG-3340, RO 32-3555, and RS 13-0830.

Autophagy inhibitors include, but are not limited to chloroquine,3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin Al,5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid,autophagy-suppressive algal toxins which inhibit protein phosphatases oftype 2A or type 1, analogues of cAMP, and drugs which elevate cAMPlevels such as adenosine, LY204002, N6-mercaptopurine riboside, andvinblastine. In addition, antisense or siRNA that inhibits expression ofproteins including but not limited to ATG5 (which are implicated inautophagy), may also be used.

The invention also relates to a method of and to a pharmaceuticalcomposition for treating a cardiovascular disease in a mammal whichcomprises an amount of a compound of the invention, or apharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative thereof, or an isotopically-labeled derivative thereof, andan amount of one or more therapeutic agents use for the treatment ofcardiovascular diseases.

Exemplary agents for use in cardiovascular disease applications areanti-thrombotic agents, e.g., prostacyclin and salicylates, thrombolyticagents, e.g., streptokinase, urokinase, tissue plasminogen activator(TPA) and anisoylated plasminogen-streptokinase activator complex(APSAC), anti-platelets agents, e.g., acetyl-salicylic acid (ASA) andclopidrogel, vasodilating agents, e.g., nitrates, calcium channelblocking drugs, anti-proliferative agents, e.g., colchicine andalkylating agents, intercalating agents, growth modulating factors suchas interleukins, transformation growth factor-beta and congeners ofplatelet derived growth factor, monoclonal antibodies directed againstgrowth factors, anti-inflammatory agents, both steroidal andnon-steroidal, and other agents that can modulate vessel tone, function,arteriosclerosis, and the healing response to vessel or organ injurypost intervention. Antibiotics can also be included in combinations orcoatings comprised by the invention. Moreover, a coating can be used toeffect therapeutic delivery focally within the vessel wall. Byincorporation of the active agent in a swellable polymer, the activeagent will be released upon swelling of the polymer.

The compounds described herein may be formulated or administered inconjunction with liquid or solid tissue barriers also known aslubricants. Examples of tissue barriers include, but are not limited to,polysaccharides, polyglycans, seprafilm, interceed and hyaluronic acid.

Medicaments which may be administered in conjunction with the compoundsdescribed herein include any suitable drugs usefully delivered byinhalation for example, analgesics, e.g. codeine, dihydromorphine,ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem;antiallergics, e.g. cromoglycate, ketotifen or nedocromil;anti-infectives, e.g. cephalosporins, penicillins, streptomycin,sulphonamides, tetracyclines or pentamidine; antihistamines, e.g.methapyrilene; anti-inflammatories, e.g. beclomethasone, flunisolide,budesonide, tipredane, triamcinolone acetonide or fluticasone;antitussives, e.g. noscapine; bronchodilators, e.g. ephedrine,adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol,phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol,salbutamol, salmeterol, terbutalin, isoetharine, tulobuterol,orciprenaline or(−)-4-amino-3,5-dichloro-a-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol;diuretics, e.g. amiloride; anticholinergics e.g. ipratropium, atropineor oxitropium; hormones, e.g. cortisone, hydrocortisone or prednisolone;xanthines e.g. aminophylline, choline theophyllinate, lysinetheophyllinate or theophylline; and therapeutic proteins and peptides,e.g. insulin or glucagon. It will be clear to a person skilled in theart that, where appropriate, the medicaments may be used in the form ofsalts (e.g. as alkali metal or amine salts or as acid addition salts) oras esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) tooptimize the activity and/or stability of the medicament.

Other exemplary therapeutic agents useful for a combination therapyinclude but are not limited to agents as described above, radiationtherapy, hormone antagonists, hormones and their releasing factors,thyroid and antithyroid drugs, estrogens and progestins, androgens,adrenocorticotropic hormone; adrenocortical steroids and their syntheticanalogs; inhibitors of the synthesis and actions of adrenocorticalhormones, insulin, oral hypoglycemic agents, and the pharmacology of theendocrine pancreas, agents affecting calcification and bone turnover:calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitaminssuch as water-soluble vitamins, vitamin B complex, ascorbic acid,fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines,chemokines, muscarinic receptor agonists and antagonists;anticholinesterase agents; agents acting at the neuromuscular junctionand/or autonomic ganglia; catecholamines, sympathomimetic drugs, andadrenergic receptor agonists or antagonists; and 5-hydroxytryptamine(5-HT, serotonin) receptor agonists and antagonists.

Therapeutic agents can also include agents for pain and inflammationsuch as histamine and histamine antagonists, bradykinin and bradykininantagonists, 5-hydroxytryptamine (serotonin), lipid substances that aregenerated by biotransformation of the products of the selectivehydrolysis of membrane phospholipids, eicosanoids, prostaglandins,thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatoryagents, analgesic-antipyretic agents, agents that inhibit the synthesisof prostaglandins and thromboxanes, selective inhibitors of theinducible cyclooxygenase, selective inhibitors of the induciblecyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin,cytokines that mediate interactions involved in humoral and cellularimmune responses, lipid-derived autacoids, eicosanoids, 3-adrenergicagonists, ipratropium, glucocorticoids, methylxanthines, sodium channelblockers, opioid receptor agonists, calcium channel blockers, membranestabilizers and leukotriene inhibitors.

Additional therapeutic agents contemplated herein include diuretics,vasopressin, agents affecting the renal conservation of water, rennin,angiotensin, agents useful in the treatment of myocardial ischemia,anti-hypertensive agents, angiotensin converting enzyme inhibitors,β-adrenergic receptor antagonists, agents for the treatment ofhypercholesterolemia, and agents for the treatment of dyslipidemia.

Other therapeutic agents contemplated include drugs used for control ofgastric acidity, agents for the treatment of peptic ulcers, agents forthe treatment of gastroesophageal reflux disease, prokinetic agents,antiemetics, agents used in irritable bowel syndrome, agents used fordiarrhea, agents used for constipation, agents used for inflammatorybowel disease, agents used for biliary disease, agents used forpancreatic disease. Therapeutic agents used to treat protozoaninfections, drugs used to treat Malaria, Amebiasis, Giardiasis,Trichomoniasis, Trypanosomiasis, and/or Leishmaniasis, and/or drugs usedin the chemotherapy of helminthiasis. Other therapeutic agents includeantimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazolequinolones, and agents for urinary tract infections, penicillins,cephalosporins, and other, β-lactam antibiotics, an agent comprising anaminoglycoside, protein synthesis inhibitors, drugs used in thechemotherapy of tuberculosis, mycobacterium avium complex disease, andleprosy, antifungal agents, antiviral agents including nonretroviralagents and antiretroviral agents.

Examples of therapeutic antibodies that can be combined with a compoundof the invention include but are not limited to anti-receptor tyrosinekinase antibodies (cetuximab, panitumumab, trastuzumab), anti CD20antibodies (rituximab, tositumomab), and other antibodies such asalemtuzumab, bevacizumab, and gemtuzumab.

Moreover, therapeutic agents used for immunomodulation, such asimmunomodulators, immunosuppressive agents, tolerogens, andimmunostimulants are contemplated by the methods herein. In addition,therapeutic agents acting on the blood and the blood-forming organs,hematopoietic agents, growth factors, minerals, and vitamins,anticoagulant, thrombolytic, and antiplatelet drugs.

Further therapeutic agents that can be combined with a compound of theinvention may be found in Goodman and Gilman's “The PharmacologicalBasis of Therapeutics” Tenth Edition edited by Hardman, Limbird andGilman or the Physician's Desk Reference, both of which are incorporatedherein by reference in their entirety.

The compounds described herein can be used in combination with theagents disclosed herein or other suitable agents, depending on thecondition being treated. Hence, in some embodiments the one or morecompounds of the invention will be co-administer with other agents asdescribed above. When used in combination therapy, the compoundsdescribed herein may be administered with the second agentsimultaneously or separately. This administration in combination caninclude simultaneous administration of the two agents in the same dosageform, simultaneous administration in separate dosage forms, and separateadministration. That is, a compound described herein and any of theagents described above can be formulated together in the same dosageform and administered simultaneously. Alternatively, a compound of theinvention and any of the agents described above can be simultaneouslyadministered, wherein both the agents are present in separateformulations. In another alternative, a compound of the presentinvention can be administered just followed by and any of the agentsdescribed above, or vice versa. In the separate administration protocol,a compound of the invention and any of the agents described above may beadministered a few minutes apart, or a few hours apart, or a few daysapart.

Administration of the compounds of the present invention can be effectedby any method that enables delivery of the compounds to the site ofaction. An effective amount of a compound of the invention may beadministered in either single or multiple doses by any of the acceptedmodes of administration of agents having similar utilities, includingrectal, buccal, intranasal and transdermal routes, by intra-arterialinjection, intravenously, intraperitoneally, parenterally,intramuscularly, subcutaneously, orally, topically, as an inhalant, orvia an impregnated or coated device such as a stent, for example, or anartery-inserted cylindrical polymer.

The amount of the compound administered will be dependent on the mammalbeing treated, the severity of the disorder or condition, the rate ofadministration, the disposition of the compound and the discretion ofthe prescribing physician. However, an effective dosage is in the rangeof about 0.001 to about 100 mg per kg body weight per day, preferablyabout 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kghuman, this would amount to about 0.05 to 7 g/day, preferably about 0.05to about 2.5 g/day. In some instances, dosage levels below the lowerlimit of the aforesaid range may be more than adequate, while in othercases still larger doses may be employed without causing any harmfulside effect, e.g. by dividing such larger doses into several small dosesfor administration throughout the day.

In some embodiments, a compound of the invention is administered in asingle dose. Typically, such administration will be by injection, e.g.,intravenous injection, in order to introduce the agent quickly. However,other routes may be used as appropriate. A single dose of a compound ofthe invention may also be used for treatment of an acute condition.

In some embodiments, a compound of the invention is administered inmultiple doses. Dosing may be about once, twice, three times, fourtimes, five times, six times, or more than six times per day. Dosing maybe about once a month, once every two weeks, once a week, or once everyother day. In another embodiment a compound of the invention and anotheragent are administered together about once per day to about 6 times perday. In another embodiment the administration of a compound of theinvention and an agent continues for less than about 7 days. In yetanother embodiment the administration continues for more than about 6,10, 14, 28 days, two months, six months, or one year. In some cases,continuous dosing is achieved and maintained as long as necessary.

Administration of the agents of the invention may continue as long asnecessary. In some embodiments, an agent of the invention isadministered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In someembodiments, an agent of the invention is administered for less than 28,14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, an agent of theinvention is administered chronically on an ongoing basis, e.g., for thetreatment of chronic effects.

When a compound of the invention, is administered in a composition thatcomprises one or more agents, and the agent has a shorter half-life thanthe compound of the invention, unit dose forms of the agent and thecompound of the invention may be adjusted accordingly.

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples moleculeswith a single chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers may be obtained by methods known to thoseskilled in the art.

EXAMPLES Example 1 Expression and Inhibition Assays of p110α/p85α,p110β/p85α, p110δ/p85α, and p110γ

Class I PI3-Ks can be either purchased (p110α/p85α, p110β/p85α,p110δ/p85α from Upstate, and p110γ from Sigma) or expressed aspreviously described (Knight et al., 2004). IC50 values are measuredusing either a standard TLC assay for lipid kinase activity (describedbelow) or a high-throughput membrane capture assay. Kinase reactions areperformed by preparing a reaction mixture containing kinase, inhibitor(2% DMSO final concentration), buffer (25 mM HEPES, pH 7.4, 10 mMMgCl2), and freshly sonicated phosphatidylinositol (100 pg/ml).Reactions are initiated by the addition of ATP containing 10 μCi ofγ-32P-ATP to a final concentration 10 or 100 μM and allowed to proceedfor 5 minutes at room temperature. For TLC analysis, reactions are thenterminated by the addition of 105 μl 1N HCl followed by 160 μlCHCl3:MeOH (1:1). The biphasic mixture is vortexed, briefly centrifuged,and the organic phase is transferred to a new tube using a gel loadingpipette tip precoated with CHCl₃. This extract is spotted on TLC platesand developed for 3-4 hours in a 65:35 solution of n-propanol:1M aceticacid. The TLC plates are then dried, exposed to a phosphorimager screen(Storm, Amersham), and quantitated. For each compound, kinase activityis measured at 10-12 inhibitor concentrations representing two-folddilutions from the highest concentration tested (typically, 200 μM). Forcompounds showing significant activity, IC50 determinations are repeatedtwo to four times, and the reported value is the average of theseindependent measurements.

Other commercial kits or systems for assaying PI3-K activities areavailable. The commercially available kits or systems can be used toscreen for inhibitors and/or agonists of PI3-Ks including but notlimited to PI 3-Kinase α, β, δ, and γ. An exemplary system is PI3-Kinase (human) HTRF™ Assay from Upstate. The assay can be carried outaccording to the procedures suggested by the manufacturer. Briefly, theassay is a time resolved FRET assay that indirectly measures PIP3product formed by the activity of a PI3-K. The kinase reaction isperformed in a microtitre plate (e.g., a 384 well microtitre plate). Thetotal reaction volume is approximately 20 ul per well. In the firststep, each well receives 2 ul of test compound in 20% dimethylsulphoxideresulting in a 2% DMSO final concentration. Next, approximately 14.5 ulof a kinase/PIP2 mixture (diluted in 1× reaction buffer) is added perwell for a final concentration of 0.25-0.3 ug/ml kinase and 10 uM PIP2.The plate is sealed and incubated for 15 minutes at room temperature. Tostart the reaction, 3.5 ul of ATP (diluted in 1× reaction buffer) isadded per well for a final concentration of 10 uM ATP. The plate issealed and incubated for 1 hour at room temperature. The reaction isstopped by adding 5 ul of Stop Solution per well and then 5 ul ofDetection Mix is added per well. The plate is sealed, incubated for 1hour at room temperature, and then read on an appropriate plate reader.Data is analyzed and IC50s are generated using GraphPad Prism 5.

Example 2 Expression and Inhibition Assays of Abl

The cross-activity or lack thereof of one or more compounds of theinvention against Abl kinase can be measured according to any proceduresknown in the art or methods disclosed below. For example, the compoundsdescribed herein can be assayed in triplicate against recombinantfull-length Abl or Abl (T315I) (Upstate) in an assay containing 25 mMHEPES, pH 7.4, 10 mM MgCl2, 200 μM ATP (2.5 μCi of γ-32P-ATP), and 0.5mg/mL BSA. The optimized Abl peptide substrate EAIYAAPFAKKK is used asphosphoacceptor (200 μM). Reactions are terminated by spotting ontophosphocellulose sheets, which are washed with 0.5% phosphoric acid(approximately 6 times, 5-10 minutes each). Sheets are dried and thetransferred radioactivity quantitated by phosphorimaging.

Example 3 Expression and Inhibition Assays of Hck

The cross-activity or lack thereof of one or more compounds of theinvention against Hck kinase can be measured according to any proceduresknown in the art or methods disclosed below. The compounds describedherein can be assayed in triplicate against recombinant full-length Hckin an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 200 μM ATP (2.5μCi of γ-32P-ATP), and 0.5 mg/mL BSA. The optimized Src family kinasepeptide substrate EIYGEFKKK is used as phosphoacceptor (200 μM).Reactions are terminated by spotting onto phosphocellulose sheets, whichare washed with 0.5% phosphoric acid (approximately 6 times, 5-10minutes each). Sheets are dried and the transferred radioactivityquantitated by phosphorimaging.

Example 4 Expression and Inhibition Assays of Insulin Receptor (IR)

The cross-activity or lack thereof of one or more compounds of theinvention against IR receptor kinase can be measured according to anyprocedures known in the art or methods disclosed below. The compoundsdescribed herein can be assayed in triplicate against recombinantinsulin receptor kinase domain (Upstate) in an assay containing 25 mMHEPES, pH 7.4, 10 mM MgCl2, 10 mM MnCl2, 200 μM ATP (2.5 μCi ofγ-32P-ATP), and 0.5 mg/mL BSA. Poly E-Y (Sigma; 2 mg/mL) is used as asubstrate. Reactions are terminated by spotting onto nitrocellulose,which is washed with 1M NaCl/1% phosphoric acid (approximately 6 times,5-10 minutes each). Sheets are dried and the transferred radioactivityquantitated by phosphorimaging.

Example 5 Expression and Inhibition Assays of Src

The cross-activity or lack thereof of one or more compounds of theinvention against Src kinase can be measured according to any proceduresknown in the art or methods disclosed below. The compounds describedherein can be assayed in triplicate against recombinant full-length Srcor Src (T338I) in an assay containing 25 mM HEPES, pH 7.4, mM MgCl2, 200μM ATP (2.5 μCi of γ-32P-ATP), and 0.5 mg/mL BSA. The optimized Srcfamily kinase peptide substrate EIYGEFKKK is used as phosphoacceptor(200 μM). Reactions are terminated by spotting onto phosphocellulosesheets, which are washed with 0.5% phosphoric acid (approximately 6times, 5-10 minutes each). Sheets were dried and the transferredradioactivity quantitated by phosphorimaging.

Example 6 Expression and Inhibition Assays of DNA-PK (DNAK)

The cross-activity or lack thereof of one or more compounds of theinvention against DNAK kinase can be measured according to anyprocedures known in the art. DNA-PK can be purchased from Promega andassayed using the DNA-PK Assay System (Promega) according to themanufacturer's instructions.

Example 7 Expression and Inhibition Assays mTOR

The ability of one or more compounds of the invention to inhibit mToractivity can be measured according to any procedures known in the art ormethods disclosed below. The compounds described herein can be testedagainst recombinant mTOR (Invitrogen) in an assay containing 50 mMHEPES, pH 7.5, 1 mM EGTA, 10 mM MgCl2, 2.5 mM, 0.01% Tween, 10 μM ATP(2.5 μCi of μ-32P-ATP), and 3 μg/mL BSA. Rat recombinant PHAS-1/4EBP1(Calbiochem; 2 mg/mL) is used as a substrate. Reactions are terminatedby spotting onto nitrocellulose, which is washed with 1M NaCl/1%phosphoric acid (approximately 6 times, 5-10 minutes each). Sheets aredried and the transferred radioactivity quantitated by phosphorimaging.

Other kits or systems for assaying mTOR activity are commerciallyavailable. For instance, one can use Invitrogen's LanthaScreen™ Kinaseassay to test the inhibitors of mTOR disclosed herein. This assay is atime resolved FRET platform that measures the phosphorylation of GFPlabeled 4EBP1 by mTOR kinase. The kinase reaction is performed in awhite 384 well microtitre plate. The total reaction volume is 20 ul perwell and the reaction buffer composition is 50 mM HEPES pH7.5, 0.01%Polysorbate 20, 1 mM EGTA, 10 mM MnCl2, and 2 mM DTT. In the first step,each well receives 2 ul of test compound in 20% dimethylsulphoxideresulting in a 2% DMSO final concentration. Next, 8 ul of mTOR dilutedin reaction buffer is added per well for a 60 ng/ml final concentration.To start the reaction, 10 ul of an ATP/GFP-4EBP1 mixture (diluted inreaction buffer) is added per well for a final concentration of 10 uMATP and 0.5 uM GFP-4EBP1. The plate is sealed and incubated for 1 hourat room temperature. The reaction is stopped by adding 10 ul per well ofa Tb-anti-pT46 4EBP1 antibody/EDTA mixture (diluted in TR-FRET buffer)for a final concentration of 1.3 nM antibody and 6.7 mM EDTA. The plateis sealed, incubated for 1 hour at room temperature, and then read on aplate reader set up for LanthaScreen™ TR-FRET. Data is analyzed andIC50s are generated using GraphPad Prism 5.

Example 8 Expression and Inhibition Assays of Vascular EndothelialGrowth Receptor

The cross-activity or lack thereof of one or more compounds of theinvention against VEGF receptor can be measured according to anyprocedures known in the art or methods disclosed below. The compoundsdescribed herein can be tested against recombinant KDR receptor kinasedomain (Invitrogen) in an assay containing 25 mM HEPES, pH 7.4, 10 mMMgCl2, 0.1% BME, 10 μM ATP (2.5 μCi of μ-32P-ATP), and 3 μg/mL BSA. PolyE-Y (Sigma; 2 mg/mL) is used as a substrate. Reactions are terminated byspotting onto nitrocellulose, which is washed with 1M NaCl/1% phosphoricacid (approximately 6 times, 5-10 minutes each). Sheets are dried andthe transferred radioactivity quantitated by phosphorimaging.

Example 9 Expression and Inhibition Assays of Ephrin Receptor B4 (EphB4)

The cross-activity or lack thereof of one or more compounds of theinvention against EphB4 can be measured according to any proceduresknown in the art or methods disclosed below. The compounds describedherein can be tested against recombinant Ephrin receptor B4 kinasedomain (Invitrogen) in an assay containing 25 mM HEPES, pH 7.4, mMMgCl2, 0.1% BME, 10 μM ATP (2.5 μCi of μ-32P-ATP), and 3 μg/mL BSA. PolyE-Y (Sigma; 2 mg/mL) is used as a substrate. Reactions are terminated byspotting onto nitrocellulose, which is washed with 1M NaCl/1% phosphoricacid (approximately 6 times, 5-10 minutes each). Sheets are dried andthe transferred radioactivity quantitated by phosphorimaging.

Example 10 Expression and Inhibition Assays of Epidermal Growth FactorReceptor (EGFR)

The cross-activity or lack thereof of one or more compounds of theinvention against EGFR kinase can be measured according to anyprocedures known in the art or methods disclosed below. The compoundsdescribed herein can be tested against recombinant EGF receptor kinasedomain (Invitrogen) in an assay containing 25 mM HEPES, pH 7.4, mMMgCl2, 0.1% BME, 10 μM ATP (2.5 μCi of μ-32P-ATP), and 3 μg/mL BSA. PolyE-Y (Sigma; 2 mg/mL) is used as a substrate. Reactions are terminated byspotting onto nitrocellulose, which is washed with 1M NaCl/1% phosphoricacid (approximately 6 times, 5-10 minutes each). Sheets are dried andthe transferred radioactivity quantitated by phosphorimaging.

Example 11 Expression and Inhibition Assays of KIT Assay

The cross-activity or lack thereof of one or more compounds of theinvention against KIT kinase can be measured according to any proceduresknown in the art or methods disclosed below. The compounds describedherein can be tested against recombinant KIT kinase domain (Invitrogen)in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 1 mM DTT, 10 mMMnCl2, 10 μM ATP (2.5 μCi of μ-32P-ATP), and 3 μg/mL BSA. Poly E-Y(Sigma; 2 mg/mL) is used as a substrate. Reactions are terminated byspotting onto nitrocellulose, which is washed with 1M NaCl/1% phosphoricacid (approximately 6 times, 5-10 minutes each). Sheets are dried andthe transferred radioactivity quantitated by phosphorimaging.

Example 12 Expression and Inhibition Assays of RET

The cross-activity or lack thereof of one or more compounds of theinvention against RET kinase can be measured according to any proceduresknown in the art or methods disclosed below. The compounds describedherein can be tested against recombinant RET kinase domain (Invitrogen)in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 2.5 mM DTT, 10μM ATP (2.5 μCi of μ-32P-ATP), and 3 μg/mL BSA. The optimized Ablpeptide substrate EAIYAAPFAKKK is used as phosphoacceptor (200 μM).Reactions are terminated by spotting onto phosphocellulose sheets, whichare washed with 0.5% phosphoric acid (approximately 6 times, 5-10minutes each). Sheets are dried and the transferred radioactivityquantitated by phosphorimaging.

Example 13 Expression and Inhibition Assays of Platelet Derived GrowthFactor Receptor (PDGFR)

The cross-activity or lack thereof of one or more compounds of theinvention against PDGFR kinase can be measured according to anyprocedures known in the art or methods disclosed below. The compoundsdescribed herein can be tested against recombinant PDG receptor kinasedomain (Invitrogen) in an assay containing 25 mM HEPES, pH 7.4, 10 mMMgCl2, 2.5 mM DTT, 10 μM ATP (2.5 μCi of μ-32P-ATP), and 3 μg/mL BSA.The optimized Abl peptide substrate EAIYAAPFAKKK is used asphosphoacceptor (200 μM). Reactions are terminated by spotting ontophosphocellulose sheets, which are washed with 0.5% phosphoric acid(approximately 6 times, 5-10 minutes each). Sheets are dried and thetransferred radioactivity quantitated by phosphorimaging.

Example 14 Expression and Inhibition Assays of FMS-Related TyrosineKinase 3 (FLT-3)

The cross-activity or lack thereof of one or more compounds of theinvention against FLT-3 kinase can be measured according to anyprocedures known in the art or methods disclosed below. The compoundsdescribed herein can be tested against recombinant FLT-3 kinase domain(Invitrogen) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2,2.5 mM DTT, 10 μM ATP (2.5 μCi of μ-32P-ATP), and 3 μg/mL BSA. Theoptimized Abl peptide substrate EAIYAAPFAKKK is used as phosphoacceptor(200 μM). Reactions are terminated by spotting onto phosphocellulosesheets, which are washed with 0.5% phosphoric acid (approximately 6times, 5-10 minutes each). Sheets are dried and the transferredradioactivity quantitated by phosphorimaging.

Example 15 Expression and Inhibition Assays of TEK Receptor TyrosineKinase (TIE2)

The cross-activity or lack thereof of one or more compounds of theinvention against TIE2 kinase can be measured according to anyprocedures known in the art or methods disclosed below. The compoundsdescribed herein can be tested against recombinant TIE2 kinase domain(Invitrogen) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 2mM DTT, 10 mM MnCl2, 10 μM ATP (2.5 μCi of μ-32P-ATP), and 3 μg/mL BSA.Poly E-Y (Sigma; 2 mg/mL) is used as a substrate. Reactions areterminated by spotting onto nitrocellulose, which is washed with 1MNaCl/1% phosphoric acid (approximately 6 times, 5-10 minutes each).Sheets are dried and the transferred radioactivity quantitated byphosphorimaging.

Example 16 B Cell Activation and Proliferation Assay

The ability of one or more compounds of the invention to inhibit B cellactivation and proliferation is determined according to standardprocedures known in the art. For example, an in vitro cellularproliferation assay is established that measures the metabolic activityof live cells. The assay is performed in a 96 well microtiter plateusing Alamar Blue reduction. Balb/c splenic B cells are purified over aFicoll-Paque™ PLUS gradient followed by magnetic cell separation using aMACS B cell Isolation Kit (Miletenyi). Cells are plated in 90 ul at50,000 cells/well in B Cell Media (RPMI+10% FBS+Penn/Strep+50 uM bME+5mM HEPES). A compound disclosed herein is diluted in B Cell Media andadded in a 10 ul volume. Plates are incubated for 30 min at 37 C and 5%CO₂ (0.2% DMSO final concentration). A 50 ul B cell stimulation cocktailis then added containing either 10 ug/ml LPS or 5 ug/ml F(ab′)2 Donkeyanti-mouse IgM plus 2 ng/ml recombinant mouse IL4 in B Cell Media.Plates are incubated for 72 hours at 37° C. and 5% CO₂. A volume of 15uL of Alamar Blue reagent is added to each well and plates are incubatedfor 5 hours at 37 C and 5% CO₂. Alamar Blue fluoresce is read at560Ex/590Em, and IC50 or EC50 values are calculated using GraphPad Prism5.

Example 17 Tumor Cell Line Proliferation Assay

The ability of one or more compounds of the invention to inhibit tumorcell line proliferation is determined according to standard proceduresknown in the art. For instance, an in vitro cellular proliferation assaycan be performed to measure the metabolic activity of live cells. Theassay is performed in a 96 well microtiter plate using Alamar Bluereduction. Human tumor cell lines are obtained from ATCC (e.g., MCF7,U-87 MG, MDA-MB-468, PC-3, and any other cell lines listed in FIG.1A-B), grown to confluency in T75 flasks, trypsinized with 0.25%trypsin, washed one time with Tumor Cell Media (DMEM+10% FBS), andplated in 90 ul at 5,000 cells/well in Tumor Cell Media. A compounddisclosed herein is diluted in Tumor Cell Media and added in a 10 ulvolume. Plates are incubated for 72 hours at 37 C and 5% CO₂. A volumeof 10 uL of Alamar Blue reagent is added to each well and plates areincubated for 3 hours at 37 C and 5% CO₂. Alamar Blue fluoresce is readat 560Ex/590Em, and IC50 values are calculated using GraphPad Prism 5.The results depicted in FIG. 1A, FIG. 1B and FIG. 7A show that acompound of the present invention effectively inhibits proliferation ofa wide range of tumor cells. In some instance, the compound of theinvention yields 50% inhibition of cell proliferation at a concentrationthat is one or two orders of magnitude less than that of a conventionalanti-cancer drug when tested under the same condition.

Example 18 Antitumor Activity In Vivo

The compounds described herein can be evaluated in a panel of human andmurine tumor models.

Paclitaxel-Refractory Tumor Models

1. Clinically-Derived Ovarian Carcinoma Model.

This tumor model is established from a tumor biopsy of an ovarian cancerpatient. Tumor biopsy is taken from the patient.

The compounds described herein are administered to nude mice bearingstaged tumors using an every 2 days×5 schedule.

2. A2780Tax Human Ovarian Carcinoma Xenograft (Mutated Tubulin).

A2780Tax is a paclitaxel-resistant human ovarian carcinoma model. It isderived from the sensitive parent A2780 line by co-incubation of cellswith paclitaxel and verapamil, an MDR-reversal agent. Its resistancemechanism has been shown to be non-MDR related and is attributed to amutation in the gene encoding the beta-tubulin protein.

The compounds described herein can be administered to mice bearingstaged tumors on an every 2 days×5 schedule.

3. HCT116/VM46 Human Colon Carcinoma Xenograft (Multi-Drug Resistant).

HCT116/VM46 is an MDR-resistant colon carcinoma developed from thesensitive HCT116 parent line. In vivo, grown in nude mice, HCT116/VM46has consistently demonstrated high resistance to paclitaxel.

The compounds described herein can be administered to mice bearingstaged tumors on an every 2 days×5 schedule.

5. M5076 Murine Sarcoma Model

M5076 is a mouse fibrosarcoma that is inherently refractory topaclitaxel in vivo.

The compounds described herein can be administered to mice bearingstaged tumors on an every 2 days×5 schedule.

One or more compounds of the invention can be used in combination othertherapeutic agents in vivo in the multidrug resistant human coloncarcinoma xenografts HCT/VM46 or any other model known in the artincluding those described herein.

It is expected that one or more compounds of the present invention arepotent inhibitors of tumor growth in vivo under the conditions tested.

Example 19 Microsome Stability Assay

The stability of one or more compounds of the invention is determinedaccording to standard procedures known in the art. For example,stability of one or more compounds of the invention is established by anin vitro assay. In particular, an in vitro microsome stability assay isestablished that measures stability of one or more compounds of theinvention when reacting with mouse, rat or human microsomes from liver.The microsome reaction with compounds is performed in 1.5 mL Eppendorftube. Each tube contains 0.1 μL of 10.0 mg/ml NADPH; 75 μL of 20.0 mg/mlmouse, rat or human liver microsome; 0.4 μL of 0.2 M phosphate buffer,and 425 μL of ddH₂O. Negative control (without NADPH) tube contains 75μL of 20.0 mg/ml mouse, rat or human liver microsome; 0.4 μL of 0.2 Mphosphate buffer, and 525 μL of ddH₂O. The reaction is started by adding1.0 μL of 10.0 mM tested compound. The reaction tubes are incubated at37° C. 100 μL sample is collected into new Eppendorf tube containing 300μL cold Methanol at 0, 5, 10, 15, 30 and 60 minutes of reaction. Samplesare centrifuged at 15,000 rpm to remove protein. Supernatant ofcentrifuged sample is transferred to new tube. Concentration of stablecompound after reaction with microsome in the supernatant is measured byLiquid Chromatography/Mass Spectrometry (LC-MS). The microsome stabilityof one or more compounds of the present invention when assayed underthis condition have T1/2 (min) well within a range required for clinicaldevelopment.

Example 20 Plasma Stability Assay

The stability of one or more compounds of the invention in plasma isdetermined according to standard procedures known in the art. See, e.g.,Rapid Commun. Mass Spectrom., 10: 1019-1026. The following procedure isan HPLC-MS/MS assay using human plasma; other species including monkey,dog, rat, and mouse are also available. Frozen, heparinized human plasmais thawed in a cold water bath and spun for 10 minutes at 2000 rpm at 4°C. prior to use. A compound of the invention is added from a 400 μMstock solution to an aliquot of pre-warmed plasma to give a final assayvolume of 400 μL (or 800 μL for half-life determination), containing 5μM test compound and 0.5% DMSO. Reactions are incubated, with shaking,for 0 minutes and 60 minutes at 37° C., or for 0, 15, 30, 45 and 60minutes at 37 C for half life determination. Reactions are stopped bytransferring 50 μL of the incubation mixture to 200 μL of ice-coldacetonitrile and mixed by shaking for 5 minutes. The samples arecentrifuged at 6000×g for 15 minutes at 4° C. and 120 μL of supernatantremoved into clean tubes. The samples are then evaporated to dryness andsubmitted for analysis by HPLC-MS/MS.

Where desired, one or more control or reference compounds (5 μM) aretested simultaneously with the test compounds: one compound,propoxycaine, with low plasma stability and another compound,propantheline, with intermediate plasma stability.

Samples are reconstituted in acetonitrile/methanol/water (1/1/2, v/v/v)and analyzed via (RP)HPLC-MS/MS using selected reaction monitoring(SRM). The HPLC conditions consist of a binary LC pump with autosampler,a mixed-mode, C12, 2×20 mm column, and a gradient program. Peak areascorresponding to the analytes are recorded by HPLC-MS/MS. The ratio ofthe parent compound remaining after 60 minutes relative to the amountremaining at time zero, expressed as percent, is reported as plasmastability. In case of half-life determination, the half-life isestimated from the slope of the initial linear range of the logarithmiccurve of compound remaining (%) vs. time, assuming first order kinetics.

Example 21 Chemical Stability

The chemical stability of one or more compounds of the invention isdetermined according to standard procedures known in the art. Thefollowing details an exemplary procedure for ascertaining chemicalstability of a subject compound. The default buffer used for thechemical stability assay is phosphate-buffered saline (PBS) at pH 7.4;other suitable buffers can be used. A compound of the invention is addedfrom a 100 μM stock solution to an aliquot of PBS (in duplicate) to givea final assay volume of 400 μL, containing 5 μM test compound and 1%DMSO (for half-life determination a total sample volume of 700 μL isprepared). Reactions are incubated, with shaking, for 0 minutes and 24hours at 37° C.; for half-life determination samples are incubated for0, 2, 4, 6, and 24 hours. Reactions are stopped by adding immediately100 μL of the incubation mixture to 100 μL of acetonitrile and vortexingfor 5 minutes. The samples are then stored at −20° C. until analysis byHPLC-MS/MS. Where desired, a control compound or a reference compoundsuch as chlorambucil (5 μM) is tested simultaneously with a compound ofthe invention of interest, as this compound is largely hydrolyzed overthe course of 24 hours. Samples are analyzed via (RP)HPLC-MS/MS usingselected reaction monitoring (SRM). The HPLC conditions consist of abinary LC pump with autosampler, a mixed-mode, C12, 2×20 mm column, anda gradient program. Peak areas corresponding to the analytes arerecorded by HPLC-MS/MS. The ratio of the parent compound remaining after24 hours relative to the amount remaining at time zero, expressed aspercent, is reported as chemical stability. In case of half-lifedetermination, the half-life is estimated from the slope of the initiallinear range of the logarithmic curve of compound remaining (%) vs.time, assuming first order kinetics.

Example 22 Akt Kinase Assay

Cells comprising components of the Akt/mTOR pathway, including but notlimited to L6 myoblasts, B-ALL cells, B-cells, T-cells, leukemia cells,bone marrow cells, p190 transduced cells, philadelphia chromosomepositive cells (Ph+), and mouse embryonic fibroblasts, are typicallygrown in cell growth media such as DMEM supplemented with fetal bovineserum and/or antibiotics, and grown to confluency.

In order to compare the effect of one or more compounds disclosed hereinon Akt activation, the selected cells are serum starved overnight andincubated with one or more compounds disclosed herein or about 0.1% DMSOfor approximately 1 minute to about 1 hour prior to stimulation withinsulin (e.g. 100 nM) for about 1 minutes to about 1 hour. Cells arelysed by scraping into ice cold lysis buffer containing detergents suchas sodium dodecyl sulfate and protease inhibitors (e.g., PMSF). Aftercontacting cells with lysis buffer, the solution is briefly sonicated,cleared by centrifugation, resolved by SDS-PAGE, transferred tonitrocellulose or PVDF and immunoblotted using antibodies to phospho-AktS473, phospho-Akt T308, Akt, and β-actin (Cell Signaling Technologies).

The results demonstrate that one or more compounds of the inventioninhibit insulin stimulated phosphorylation of Akt at S473.Alternatively, some compounds of the invention additionally inhibitinsulin stimulated phosphorylation of Akt at T308. The class ofcompounds that can inhibit Akt signalling more effectively thanrapamycin as shown herein include those (e.g., compounds shown inTable 1) that inhibit mTORC2 and mTORC1.

Example 23 Kinase Signaling in Blood

PI3K/Akt/mTor signaling is measured in blood cells using the phosflowmethod (Methods Enzymol. 2007; 434:131-54). The advantage of this methodis that it is by nature a single cell assay so that cellularheterogeneity can be detected rather than population averages. Thisallows concurrent distinction of signaling states in differentpopulations defined by other markers. Phosflow is also highlyquantitative. To test the effects of one or more compounds of theinvention, unfractionated splenocytes, or peripheral blood mononuclearcells are stimulated with anti-CD3 to initiate T-cell receptorsignaling. The cells are then fixed and stained for surface markers andintracellular phosphoproteins. It is expected that inhibitors disclosedherein inhibit anti-CD3 mediated phosphorylation of Akt-S473 and S6,whereas rapamycin inhibits S6 phosphorylation and enhances Aktphosphorylation under the conditions tested.

Similarly, aliquots of whole blood are incubated for 15 minutes withvehicle (e.g. 0.1% DMSO) or kinase inhibitors at various concentrations,before addition of stimuli to crosslink the T cell receptor (TCR)(anti-CD3 with secondary antibody) or the B cell receptor (BCR) usinganti-kappa light chain antibody (Fab′2 fragments). After approximately 5and 15 minutes, samples are fixed (e.g. with cold 4% paraformaldehyde)and used for phosflow. Surface staining is used to distinguish T and Bcells using antibodies directed to cell surface markers that are knownto the art. The level of phosphorylation of kinase substrates such asAkt and S6 are then measured by incubating the fixed cells with labeledantibodies specific to the phosphorylated isoforms of these proteins.The population of cells is then analyzed by flow cytometery. The resultsare expected to show that one or more of the compounds of the inventioncan selectively inhibit signaling of one or more members of PI3K, mTOR,and Akt in blood cells under the conditions tested.

Example 24 Colony Formation Assay

Murine bone marrow cells freshly transformed with a p190 BCR-Ablretrovirus (herein referred to as p190 transduced cells) are plated inthe presence of various drug combinations in M3630 methylcellulose mediafor about 7 days with recombinant human IL-7 in about 30% serum, and thenumber of colonies formed is counted by visual examination under amicroscope. It is expected that compounds of the invention potentiatethe effects of a half maximal concentration of known chemotherapeuticagents such as and without limitation imatinib, rapamycin, and dasatinibat the concentrations examined.

Alternatively, human peripheral blood mononuclear cells are obtainedfrom Philadelphia chromosome positive (Ph+) and negative (Ph−) subjectsupon initial diagnosis or relapse. Live cells are isolated and enrichedfor CD19+ CD34+ B cell progenitors. After overnight liquid culture,cells are plated in methocult GF+ H4435, Stem Cell Technologies)supplemented with cytokines (IL-3, IL-6, IL-7, G-CSF, GM-CSF, CF, Flt3ligand, and erythropoietin) and various concentrations of knownchemotherapeutic agents in combination with either compounds of theinvention. Colonies are counted by microscopy 12-14 days later. Thismethod can be used to test for the additive or synergistic activity ofvarious combination therapies utilizing the subject composition. It isexpected that one or more the compounds of the present invention arepotent and selective inhibitors of p190 transduced cell colony formationunder the conditions tested.

Example 25 In Vivo Effect of Kinase Inhibitors on Leukemic Cells

Female recipient mice are lethally irradiated from a γ source in twodoses about 4 hr apart, with approximately 5 Gy each. About 1 hr afterthe second radiation dose, mice are injected i.v. with about 1×10⁶leukemic cells (e.g. Ph+ human or murine cells, or p190 transduced bonemarrow cells). These cells are administered together with aradioprotective dose of about 5×10⁶ normal bone marrow cells from 3-5week old donor mice. Recipients are given antibiotics in the water andmonitored daily. Mice who become sick after about 14 days are euthanizedand lymphoid organs are harvested for analysis. Kinase inhibitortreatment begins about 10 days after leukemic cell injection andcontinues daily until the mice become sick or a maximum of approximately35 days post-transplant. Inhibitors are given by oral lavage.

Peripheral blood cells are collected approximately on day 10(pre-treatment) and upon euthanization (post treatment), contacted withlabeled anti-hCD4 antibodies and counted by flow cytometry. This methodcan be used to demonstrate that the synergistic effect of one or morecompounds of the invention alone or in combination with knownchemotherapeutic agents significantly reduce leukemic blood cell countsas compared to treatment with known chemotherapeutic agents (e.g.Gleevec) alone under the conditions tested.

Example 26 Inhibition of Proliferation of Tumor Cells Deficient in PTENActivity but Expressing PI3-Kinases

The ability of one or more compounds of the invention to inhibitproliferation of tumor cells deficient in PTEN Activity but expressingPI3-kinases is tested according to the procedure detailed in example 17.As is shown in FIG. 7A, a compound of the present invention (e.g., acompound of Table 1) yields 50% inhibition of PC-3 cell proliferation ata concentration that is at least about two orders of magnitude less ascompared to rapamycin.

Western blot analysis revealed that the compound of the invention iscapable of inhibiting phosphorylation of AKT (S473) and AKT (T308) aswell as other downstream targets of the mTor signaling pathway to agreater degree than rapamycin. See FIG. 7B. In particular, PC-3 cellswere plated at about 1×10⁵ cells/well in 24 well plates in a culturemedia containing 10% FBS. The cells were allowed to grow to about 80%confluent. Cells were treated for 2 hours at 37° C. in CO₂ incubatorwith fresh cell culture media (10% FBS) with a compound of the presentinvention or rapamycin at indicated concentrations. After incubation,cells were lysed by adding 1× Cell Lysis Buffer (200 μl per well of24-well plate of confluent cells). Proteins were separated via SDS-PAGEon 4-20% gradient gels and standard semi-dry blotting techniques areused to transfer the protein to nitrocellulose membranes. p-AKT(473),p-S6K, and p-4EBP1 were detected by using rabbit anti-human primaryantibodies (Cell Signaling, Danvers, Mass.) followed by anHRP-conjugated anti-rabbit secondary antibody (Cell Signaling, Danvers,Mass.). The LumiGLO substrate (KPL, Inc., Gaithersburg, Md.) is used todetect the phospho-proteins on the Western blot.

Example 27 Treatment of Lupus Disease Model Mice

Mice lacking the inhibitory receptor FcγRIIb that opposes PI3K signalingin B cells develop lupus with high penetrance. FcγRIIb knockout mice(R2KO, Jackson Labs) are considered a valid model of the human diseaseas some lupus subjects show decreased expression or function of FcγRIIb(S. Bolland and J. V. Ravtech 2000. Immunity 12:277-285).

The R2KO mice develop lupus-like disease with anti-nuclear antibodies,glomerulonephritis and proteinurea within about 4-6 months of age. Forthese experiments, the rapamycin analogue RAD001 (available from LCLaboratories) is used as a benchmark compound, and administered orally.This compound has been shown to ameliorate lupus symptoms in theB6.Slelz.Sle3z model (T. Wu et al. J. Clin Invest. 117:2186-2196).

Lupus disease model mice such as R2KO, BXSB or MLR/lpr are treated atabout 2 months old, approximately for about two months. Mice are givendoses of: vehicle, RAD001 at about 10 mg/kg, or compounds disclosedherein at approximately 10 mg/kg to about 50 mg/kg. Blood and urinesamples are obtained at approximately throughout the testing period, andtested for antinuclear antibodies (in dilutions of serum) or proteinconcentration (in urine). Serum is also tested for anti-ssDNA andanti-dsDNA antibodies by ELISA. Animals are euthanized at day 60 andtissues harvested for measuring spleen weight and kidney disease.Glomerulonephritis is assessed in kidney sections stained with H&E.Other animals are studied for about two months after cessation oftreatment, using the same endpoints.

This model established in the art can be employed to test that thekinase inhibitors disclosed herein can suppress or delay the onset oflupus symptoms in lupus disease model mice.

Example 28 Murine Bone Marrow Transplant Assay

Female recipient mice are lethally irradiated from a γ ray source. About1 hr after the radiation dose, mice are injected with about 1×10⁶leukemic cells from early passage p190 transduced cultures (e.g. asdescribed in Cancer Genet Cytogenet. 2005 August; 161(1):51-6). Thesecells are administered together with a radioprotective dose ofapproximately 5×106 normal bone marrow cells from 3-5 wk old donor mice.Recipients are given antibiotics in the water and monitored daily. Micewho become sick after about 14 days are euthanized and lymphoid organsharvested for flow cytometry and/or magnetic enrichment. Treatmentbegins on approximately day 10 and continues daily until mice becomesick, or after a maximum of about 35 days post-transplant. Drugs aregiven by oral gavage (p.o.). In a pilot experiment a dose ofchemotherapeutic that is not curative but delays leukemia onset by aboutone week or less is identified; controls are vehicle-treated or treatedwith chemotherapeutic agent, previously shown to delay but not cureleukemogenesis in this model (e.g. imatinib at about 70 mg/kg twicedaily). For the first phase p190 cells that express eGFP are used, andpostmortem analysis is limited to enumeration of the percentage ofleukemic cells in bone marrow, spleen and lymph node (LN) by flowcytometry. In the second phase, p190 cells that express a tailless formof human CD4 are used and the postmortem analysis includes magneticsorting of hCD4+ cells from spleen followed by immunoblot analysis ofkey signaling endpoints: p Akt-T308 and S473; pS6 and p4EBP-1. Ascontrols for immunoblot detection, sorted cells are incubated in thepresence or absence of kinase inhibitors of the present disclosureinhibitors before lysis. Optionally, “phosflow” is used to detect p Akt—S473 and pS6-S235/236 in hCD4-gated cells without prior sorting. Thesesignaling studies are particularly useful if, for example, drug-treatedmice have not developed clinical leukemia at the 35 day time point.Kaplan-Meier plots of survival are generated and statistical analysisdone according to methods known in the art. Results from p190 cells areanalyzed separated as well as cumulatively.

Samples of peripheral blood (100-200 μl) are obtained weekly from allmice, starting on day 10 immediately prior to commencing treatment.Plasma is used for measuring drug concentrations, and cells are analyzedfor leukemia markers (eGFP or hCD4) and signaling biomarkers asdescribed herein. It is expected that the results of the analysisdemonstrate effective therapeutic doses of the compounds disclosedherein for inhibiting the proliferation of leukemic cells. It is furtherexpected that combination therapy of the inhibitors disclosed hereinwith other chemotherapeutic agents including but not limited to thosedisclosed herein (e.g. Gleevec and dasatinib) exhibit a greater degreeof efficacy or decreased toxicity in comparison to the use of a singlechemotherapeutic agent.

Example 29 Rodent Pharmacokinetic Assay

In order to study the pharmacokinetics of the compounds of the inventiona set of 4-10 week old mice are grouped according to the followingtable:

Compound Administration Mice/ from day-1 to day-7 Group# group (mg/kg)Route Regimen 1 3 1 Po BID for 7 2 3 3 days 3 3 10 4 3 30 5 3 60

Alternatively, compounds are dosed acutely (e.g. once) and after a time(e.g. about 0, 30 s, 1 m, 5 m, 10 m, 20 m, 30 m, 1 hr, 2 hr, 3 hr, 5 hr,8 hr, 10 hr, 12 hr, 1 d, 2 d, etc.) blood is collected and analyzed asdescribed below.

Compounds of the invention are dissolved in an appropriate vehicle (e.g.5% 1-methyl-2-pyrrolidinone, 85% polyethylene glycol 400, 10% Solutor)and administered orally at 12 hour intervals daily. All animals areeuthanized in CO₂ 2 hours after the final compound is administered.Blood is collected immediately and kept on ice for plasma isolation.Plasma is isolated by centrifuging at 5000 rpm for 10 minutes. Harvestedplasma is frozen for pharmacokinetic detection.

The results are expected to demonstrate the pharmacokinetic parameterssuch as absorption, distribution, metabolism, excretion, and toxicityfor the compounds of the invention.

Example 30 Combination use of PI3Kδ Inhibitors and Agents that InhibitIgE Production or Activity

The compounds of the invention may present synergistic or additiveefficacy when administered in combination with an inhibitors selectivefor one or more PI3-kinase, e.g., PI3Kδ.

PI3Kδ inhibitors may be efficacious in treatment of autoimmune andinflammatory disorders (AIID) for example rheumatoid arthritis. When aPI3Kδ inhibitor cause an undesired level of IgE production, one maychoose to administer it in combination with an agent that inhibits IgEproduction or IgE activity such as an mTORC1 and/or mTORC2 inhibitordisclosed herein. Additionally, the administration of PI3Kδ or PI3Kδ/γinhibitors in combination with inhibitors of mTOR may also exhibitsynergy through enhanced inhibition of the PI3K pathway. Various in vivoand in vitro models may be used to establish the effect of suchcombination treatment on AIID including but not limited to (a) in vitroB-cell antibody production assay, (b) in vivo TNP assay, and (c) rodentcollagen induced arthritis model.

(a) B-Cell Assay

Mice are euthanized, and the spleens are removed and dispersed through anylon mesh to generate a single-cell suspension. The splenocytes arewashed (following removal of erythrocytes by osmotic shock) andincubated with anti-CD43 and anti-Mac-1 antibody-conjugated microbeads(Miltenyi Biotec). The bead-bound cells are separated from unbound cellsusing a magnetic cell sorter. The magnetized column retains the unwantedcells and the resting B cells are collected in the flow-through.Purified B-cells are stimulated with lipopolysaccharide or an anti-CD40antibody and interleukin 4. Stimulated B-cells are treated with vehiclealone or with a PI3Kδ inhibitor with and without mTOR inhibitors such asrapamycin, rapalogs, or mTORC1/C2 inhibitors disclosed herein. Theresults are expected to show that in the presence of mTOR inhibitorsalone (e.g., rapamycin as well as the subject inhibitors capable ofinhibiting both mTORC1 and mTORC2), there is little to no substantialeffect on IgG and IgE response. However, in the presence of PI3Kδ andmTOR inhibitors, the B-cells are expected to exhibit a decreased IgGresponse as compared to the B-cells treated with vehicle alone, and theB-cells are expected to exhibit a decreased IgE response as compared tothe response from B-cells treated with PI3Kδ inhibitors alone.

(b) TNP Assay

Mice are immunized with TNP-Ficoll or TNP-KHL and treated with: vehicle,a PI3Kδ inhibitor, an mTOR inhibitor, for example rapamycin, or a PI3Kδinhibitor in combination with an mTOR inhibitor such as rapamycin.Antigen-specific serum IgE is measured by ELISA using TNP-BSA coatedplates and isotype specific labeled antibodies. This assay can be usedto test that mice treated with an mTOR inhibitor alone exhibit little orno substantial effect on antigen specific IgG3 response and nostatistically significant elevation in IgE response as compared to thevehicle control. This assay can also be used to test that mice treatedwith both PI3Kδ inhibitor and mTOR inhibitor exhibit a reduction inantigen specific IgG3 response as compared to the mice treated withvehicle alone. Additionally, this assay can be employed to test that themice treated with both PI3Kδ inhibitor and mTOR inhibitor exhibit adecrease in IgE response as compared to the mice treated with PI3Kδinhibitor alone.

(c) Rat Collagen Induced Arthritis Model

Female Lewis rats are anesthetized and given collagen injectionsprepared and administered as described previously on day 0. On day 6,animals are anesthetized and given a second collagen injection. Calipermeasurements of normal (pre-disease) right and left ankle joints areperformed on day 9. On days 10-11, arthritis typically occurs and ratsare randomized into treatment groups. Randomization is performed afterankle joint swelling is obviously established and there is good evidenceof bilateral disease.

After an animal is selected for enrollment in the study, treatment isinitiated. Animals are given vehicle, PI3Kδ inhibitor, or PI3Kδinhibitor in combination with an mTOR inhibitor. Dosing is administeredon days 1-6. Rats are weighed on days 1-7 following establishment ofarthritis and caliper measurements of ankles taken every day. Final bodyweights are taken on day 7 and animals are euthanized.

This assay can be used to test that the combination treatment usingPI3Kδ inhibitor and an inhibitor of mTOR provides greater efficacy thantreatment with PI3Kδ inhibitor alone.

Example 31 Inhibition of Tumor Growth In Vivo

Cell Lines:

Tumor cell lines such as A549, U87, ZR-75-1 and 786-0 are obtained fromAmerican Type Culture Collection (ATCC, Manassas, Va.). Cells areproliferated and preserved cryogenically at early passage (e.g. passage3). One aliquot is used for further proliferation to get enough cellsfor one TGI study (at about passage 9). Animals

Female athymic nude mice are supplied by Harlan. Mice are received at 4to 6 weeks of age. All mice are acclimated for about one day to twoweeks prior to handling. The mice are housed in microisolator cages andmaintained under specific pathogen-free conditions. The mice are fedwith irradiated mouse chow and freely available autoclaved water isprovided.

Tumor Xenograft Model:

Mice are inoculated subcutaneously in the right flank with 0.01 to 0.5ml of tumor cells such as those listed above (approximately 1.0×10⁵ to1.0×10⁸ cells/mouse). Five to 10 days following inoculation, tumors aremeasured using calipers and tumor weight is calculated, for exampleusing the animal study management software, such as Study DirectorV.1.6.70 (Study Log). Mice with tumor sizes of about 120 mg arepair-matched into desired groups using Study Director (Day 1). Bodyweights are recorded when the mice are pair-matched. Tumor volume andbodyweight measurements are taken one to four times weekly and grossobservations are made at least once daily. On Day 1, compounds of thepresent invention and reference compounds as well as vehicle control areadministered by oral gavage or iv as indicated. At the last day of theexperiment, mice are sacrificed and their tumors are collected 1-4 hoursafter the final dose. The tumors are excised and cut into two sections.One third of the tumor is fixed in formalin and embedded in paraffinblocks and the remaining two thirds of tumor is snap frozen and storedat −80° C.

Data and Statistical Analysis:

Mean tumor growth inhibition (TGI) is calculated utilizing the followingformula:

Tumors that regress from the Day 1 starting size are removed from thecalculations. Individual tumor shrinkage (TS) is calculated using theformula below for tumors that show regression relative to Day 1 tumorweight. The mean tumor shrinkage of each group is calculated andreported.

The model can be employed to show whether the compounds of the inventioncan inhibit tumor cell growth including but not limited to renalcarcinoma cell growth, breast cancer cell growth, lung cancer cellgrowth, or glioblastoma cell growth under the conditions tested.

${TS} = {\left\lbrack {1 - \frac{\left( {{Tumor}\mspace{14mu} {Weight}_{({Final})}} \right)}{\left( {{Tumor}\mspace{14mu} {Weight}_{({{Day}\mspace{14mu} 1})}} \right.}} \right\rbrack \times 100\%}$

As shown in FIGS. 3A-3B, a compound of the invention of Formula I′-A′reduces tumor size in the U87 human glioblastoma xenograft model in adose dependent manner over a period of 14-day treatment. FIG. 3C showsthat the compound has no substantial toxic effect on the animal as therewas no significant weight loss during the treatment. Excised tumors(FIG. 3C) were further examined by Western blot analysis which revealedinhibition of mTOR/Akt signalling by the compound of the invention(FIGS. 4B and 10). In particular, inhibition of mTOR/Akt signalling wasevidenced by a decrease in phosphorylated Akt at residues S473 and T308,pS6, p4EBP-1, and Cyclin D1. The compound of the invention is morepotent in inhibiting mTOR/Akt signalling as compared to an inhibitorthat is not selective for mTORs, such as one commonly referred to asPanPI3K/mTor inhibitor. The excised tumors were also subject to TUNELstaining (FIG. 12) which shows tumor cell death after the treatment.

The same experiment was performed with several other tumor modelsincluding tumor cell A549 induced NSCLC (non-small cell lung cancer),tumor cell ZR-75-1 induced breast cancer, and tumor cell 786-O inducedRCC (renal cell carcinoma). FIGS. 11B-11D indicate that the efficacy ofthe compound of the invention in treating all of these tumors becamedetectable as early as one week after treatment. The effect of reductionin tumor size in all instances last at least 1 month.

1. A method of treating a disorder comprising administering to a subject in need thereof an effective amount of an isolated compound or pharmaceutically acceptable salt of a compound of Formula II-A-1:

or a pharmaceutically acceptable salt thereof, wherein: X₁ is N and X₂ is N; R₁ is hydrogen, -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkylheterocyclyl, -L-heteroalkyl or -L-heterocyclyl, each of which is unsubstituted or substituted by one or more independent R³ substituents; L is a bond, C═O, —C(═O)O—, —C(═O)N(R³¹)—, —S—, —S(O)—, —S(O)₂—, —S(O)₂N(R³¹)—, or —N(R³¹)—; k is 1: E² is H; W² is —O—, —NR⁷—, —S(O)₀₋₂—, —C(O)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—, —N(R⁷)C(O)N(R⁸)—, —N(R⁷)S(O)—, —N(R⁷)S(O)₂—, —C(O)O—, —CH(R⁷)N(C(O)OR⁸)—, —CH(R⁷)N(C(O)R⁸)—, —CH(R⁷)N(SO₂R⁸)—, —CH(R⁷)N(R⁸)—, —CH(R⁷)C(O)N(R⁸)—, —CH(R⁷)N(R⁸)C(O)—, —CH(R⁷)N(R⁸)S(O)—, or —CH(R⁷)N(R⁸)S(O)₂—; R³ is hydrogen, halogen , —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, or —CO₂R³¹; R² is hydrogen, halogen, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═(O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂C(═O)SR³³, —NR³¹(C═NR³²)NR³³R³², —NR³¹C(═NR)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³², bicyclic aryl, substituted monocyclic aryl, hetaryl, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₁₋₁₀alkyl-C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₁₀alkyl, C₃₋₈cycloalkyl-C₂₋₁₀alkenyl, C₃₋₈cycloalkyl-C₂₋₁₀alkynyl, C₂₋₁₀alkyl-monocyclic aryl, monocyclic aryl-C₂₋₁₀alkyl, C₁₋₁₀alkylbicycloaryl, bicycloaryl-C₁₋₁₀alkyl, substituted C₁₋₁₀alkylaryl, substituted aryl-C₁₋₁₀alkyl, C₁₋₁₀alkylhetaryl, C₁₋₁₀alkylheterocyclyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₂₋₁₀alkenylaryl, C₂₋₁₀alkenylhetaryl, C₂₋₁₀alkenylheteroalkyl, C₂₋₁₀alkenylheterocycicyl, C₂₋₁₀alkynylaryl, C₂₋₁₀alkynylhetaryl, C₂₋₁₀alkynylheteroalkyl, C₂₋₁₀alkynylheterocylyl, C₂₋₁₀alkenyl-C₃₋₈cycloalkyl, C₂₋₁₀alkynyl-C₃₋₈cycloalkenyl, C₁₋₁₀alkoxy C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl, heterocyclyl, heterocyclyl C₁₋₁₀alkyl, heterocyclylC₂₋₁₀alkenyl, heterocyclyl-C₂₋₁₀alkynyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl, aryl-heterocyclyl, hetaryl-C₁₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, hetaryl-C₂₋₁₀alkynyl, hetaryl-C₃₋₈cycloalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein each of said bicyclic aryl, monocyclic aryl, or heteroaryl moiety is unsubstituted or is substituted with one or more independent halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹R³², —C(═O)NR³⁴R³⁵, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —SO₂NR³⁴R³⁵, —NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O )NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³³, —NR³¹C(═NR³²)NR³³R³², —NR³¹C(═NR³²)OR³³, —NR³¹C(N═NR³²)SR³³, —OC(═O)OR³³, —C(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹R³², and wherein each of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or is substituted with one or more halo, —OH, —R³¹, —CF₃, —OCF₃, —OR³¹, —O-aryl, —NR³¹R³², —NR³⁴R³⁵, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³⁴R³⁵, or —C(═O)NR³¹R³²; each of R³¹, R³², and R³³ is independently H or unsubstituted C₁₋₁₀alkyl; R³⁴ and R³⁵ in —NR³⁴R³⁵, —C(═O)NR³⁴R³⁵, or —SO₂NR³⁴R³⁵, are taken together with the nitrogen atom to which they are attached to form a 3-10 membered saturated or unsaturated ring; wherein said ring is independently unsubstituted or is substituted by one or more —NR³¹R³², hydroxyl, halogen, oxo, aryl, hetaryl, C₁₋₆alkyl, or O-aryl, and wherein said 3-10 membered saturated or unsaturated ring independently contains 0, 1, or 2 more heteroatoms in addition to the nitrogen atom; and each of R⁷ and R⁸ is independently hydrogen or C₁₋₁₀alkyl.
 2. The method according to claim 1, wherein R₁ is -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkylheterocyclyl, or -L-heterocyclyl, each of which is unsubstituted or substituted by one or more independent R³ substituents; and R³ is hydrogen, —OH, —OR³¹, —NR³¹R³², or —C(O)R³¹.
 3. The method according to claim 1, wherein W² is —NR⁷—, —N(R⁷)C(O)—, or —N(R⁷)S(O)₂—, and wherein R⁷ is hydrogen.
 4. The method according to claim 1, wherein R₂ is H.
 5. The method according to claim 1, wherein R₁ is -L-C₁₋₁₀alkyl or -L-C₃₋₈cycloalkyl, each of which is unsubstituted or substituted by one or more independent R³ substituents, wherein R³ is hydrogen, —OH, —OR³¹, or —C(O)R³¹.
 6. The method according to claim 1, 36 or 38, wherein said disorder is selected from the group consisting of hyperproliferative disorder, bone disorder, inflammatory disease, immune disease, nervous system disease, metabolic disease, angiogenic disease, ophthalmic disease, respiratory disease, and cardiac disease.
 7. The method according to claim 6, wherein said hyperproliferative disorder is cancer.
 8. The method according to claim 7, wherein said cancer is selected from the group consisting of fibrosarcoma, pancreatic cancer, renal cancer, liver cancer, melanoma, nasopharyngeal cancer, gastric cancer, ovarian cancer, leukemia, myeloma, breast cancer, prostate cancer, colorectal cancer, lung cancer, glioblastoma, uterine cancer, bladder cancer, mesothelioma, head cancer, neck cancer, and cervical cancer.
 9. The method according to claim 8, wherein said cancer is renal cancer.
 10. The method according to claim 9, wherein said renal cancer is renal cell carcinoma.
 11. The method according to claim 8, wherein said cancer is breast cancer.
 12. The method according to claim 8, wherein said cancer is uterine cancer.
 13. The method according to claim 8, wherein said cancer is bladder cancer.
 14. The method according to claim 8, wherein said cancer is colorectal cancer.
 15. The method according to claim 8, wherein said cancer is lung cancer.
 16. The method according to claim 8, wherein said cancer is glioblastoma.
 17. The method according to claim 6, wherein said disorder is mediated by a protein kinase or a lipid kinase.
 18. The method according to claim 17, wherein said protein kinase is mTorC1 and/or mTorC2.
 19. The method according to claim 6, further comprising administering a second biologically active agent.
 20. The method according to claim 19, wherein said biologically active agent is an anti-cancer agent.
 21. The method according to claim 20, wherein said anti-cancer agent is an anti-hormone.
 22. The method according to claim 21, wherein said anti-hormone is an anti-estrogen.
 23. The method according to claim 20, wherein said anti-cancer agent is a growth factor inhibitor.
 24. The method according to claim 23, wherein said growth factor inhibitor is herceptin.
 25. The method according to claim 20, wherein said anti-cancer agent is an angiogenesis inhibitor.
 26. The method according to claim 25, wherein said angiogenesis inhibitor is bevacizumab and trastuzumab.
 27. The method according to claim 25, wherein said angiogenesis inhibitor is sorafenib.
 28. The method according to claim 20, wherein said anti-cancer agent is a mitotic inhibitor.
 29. The method according to claim 28, wherein said mitotic inhibitor is paclitaxel or docetaxel.
 30. The method according to claim 8, wherein said cancer is prostate cancer.
 31. The method according to claim 12, wherein said cancer is endometrial cancer.
 32. The method according to claim 21, wherein said anti-hormone is an anti-androgen.
 33. The method according to claim 20, wherein said anti-cancer agent is an antimetabolite.
 34. The method according to claim 33, wherein said antimetabolite is gemcitabine.
 35. The method according to claim 1, wherein R³¹ and R³² are each H.
 36. The method according to claim 1, wherein the compound is

wherein R₁ is -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, -L-C₁₋₁₀alkylheterocyclyl, or -L-heterocyclyl, each of which is unsubstituted or substituted by one or more independent R³ substituents; and R³ is hydrogen, —OH, —OR³¹, —NR³¹R³², or —C(O)R³¹.
 37. The method according to claim 1, wherein the compound is

wherein R₁ is -L-C₁₋₁₀alkyl, -L-C₃₋₈cycloalkyl, or -L-C₁₋₁₀alkylheterocyclyl.
 38. The method according to claim 37, wherein R₁ is isopropyl.
 39. The method according to claim 37, wherein R₁ is 